2020 June AANnews

VOLUME 33 · ISSUE 6 · JUNE 2020

Visit AAN.com/Covid19 for the latest pandemic information and resources to support you and your crucial work.

VIRTUAL SCIENTIFIC PRESENTATIONS DEBUT ON NEW PLATFORM Free Access to up to 3,000 Presentations The AAN has launched a new platform to showcase both oral and poster presentations virtually—13 of which are part of the Emerging Science Program. The new 2020 AAN Science Highlights are available free to both AAN members and nonmembers at AAN.com/2020science.

“Science is all about communication,” said AAN Science Committee Chair Natalia S. Rost, MD, MPH, FAAN, FAHA. “The most important aspect of being involved in research Rost is the ability to present your work to your peers, to receive feedback, and to be able to improve your science in response accordingly. The questions and comments from our peers make us dig deeper into the problem we investigate, re-think methodological approaches, and seek new meaning to our findings.

Nothing can substitute for this type of scientific exchange—and while we are not able to replicate our usual vibrant Annual Meeting scientific experience, I highly recommend to our members to engage with the abstract authors Continued on page 9

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AAN Offers Ethical Guidance Regarding Patients and COVID-19 Pandemic

NeuroReady Offers Convenient, Comprehensive Review and Update in Neurology

The AAN has issued new ethical guidance for neurologists and neuroscience professionals caring for neurology patients during the COVID-19 pandemic. The new position statement was published in the May 15, 2020, online issue of Neurology® at n.Neurology.org. The position statement was Continued on page 19

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New Neurology Question of the Day Mobile App Now Available

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Get a comprehensive review and update on the latest neurology science and therapies with the AAN’s suite of online NeuroReady courses. These go-to educational resources feature a convenient online format and include 12 months of access that allow you to complete the programs in your own time and at your own pace.

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Continuum Explores Neurology of Systemic Disease

Continued on page 9

22 AAN Members Advocate,

Educate on COVID-19 Issues

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In Multiple

Sclerosis

GREY MATTERS, TOO Learn more about Grey Matter pathology

MSGreyandWhite.com

Research has revealed that Grey Matter pathology… BEGINS EARLY 1-3

IS WIDESPREAD4-6

DRIVES DISEASE ACTIVITY 7

IS LARGELY INDEPENDENT OF WHITE MATTER PATHOLOGY8,9

References: 1. Geurts JJG, Calabrese M, Fisher E, Rudick RA. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol. 2012;11(12):1082-1092. 2. Chard D, Miller D. Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging. J Neurol Sci. 2009;282(1-2):5-11. 3. Crespy L, Zaaraoui W, Lemaire M, et al. Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging. PLoS ONE. 2011;6(9):e24969.

4. van de Pavert SHP, Muhlert N, Sethi V, et al. DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime?

J Neurol Neurosurg Psychiatry. 2015;87(5):461-467. 5. Fisher E, Lee J-C, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol. 2008;64(3):255-265. 6. Hulst HE, Geurts JJG. Gray matter imaging in multiple sclerosis: what have we learned? BMC Neurology. 2011;153(11):1-11. 7. Eshaghi A, Prados F, Brownlee WJ, et al; on behalf of the MAGNIMS study group. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222. 8. BÜ L, Geurts JJG, van der Valk P, Polman C, Barkhof F. Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol. 2007;64(1):76-80. 9. Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn). 2013;19(4):901-921. Š 2020 Bristol-Myers Squibb Company. All rights reserved. Printed in the USA. 03/20 US-CLG-20-0491

AANnews · June 2020

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

18

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

For AAN Transforming Leaders Program graduate Aiesha Ahmed, MD, honing the ability to see herself as part of a larger whole and not focus simply on her role proved a career-altering revelation.

Contact Information American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415 Phone: (800) 879-1960 (toll free) (612) 928-6000 (international) Email:

memberservices@aan.com

Website: AAN.com J U N E/J U LY 2 0 2 0

For advertising rates, contact: Eileen R. Henry Wolters Kluwer Health | Medical Research Lippincott, Williams & Wilkins Phone: (732) 778-2261 Email: Eileen.Henry@wolterskluwer.com

AAN Chief Executive Officer: Mary E. Post, MBA, CAE

Editor-in-Chief: Melissa W. Ko, MD, FAAN, CPE Managing Editor: Angela M. Babb, MS, CAE, APR Editor: Tim Streeter Writers: Ryan Knoke and Sarah Parsons Designer: Siu Lee Email: aannews@aan.com AANnews® is published monthly by the American Academy of Neurology for its 36,000 members worldwide.

Access this magazine and other AAN publications online at AAN.com.

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

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

The inclusion of advertisements and/or promotions of Sponsors and other Internet sites or resources that offer content, goods, or services on the Website does not imply endorsement of the advertised/promoted products or services by AAN.

Transforming Leaders Program Helps Graduate See Herself as Part of Bigger Picture

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Ways to Manage Anxiety Nutrition Diet Is Key During COVID-19

Telehealth Make the Most of a Virtual Visit Exercise 8 Ways to Stay Active at Home

COVID-19 Heroes We salute health care workers like neurologist Dr. James Conners on the front lines of care.

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Brain & Life Helps Readers Cope with COVID-19

This month’s issue is devoted to COVID-19, starting with the cover story on how patients’ experiences in hospitals have changed and what neurologists and other health care workers are doing to treat patients and keep them safe during this critical time.

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Strong Results Shown in 2019 MIPS Submission Summary

During the 2019 MIPS submission period, a total of 73 practices submitted their MIPS reporting through the Axon Registry.

News Briefs Academy’s COVID-19 Resources Highlighted by Federal Agency The AAN recently held a meeting with COVID-19 response staff at the Department of Health and Human Services (HHS) to discuss the challenges facing neurologists and their needs during COVID-19. Recognizing the AAN’s expertise and leadership in telehealth, following the meeting, the AAN was invited to present resources that we have developed related to telehealth implementation to an HHS workgroup aimed at providing support to officebased providers. The AAN’s thought leadership in this area is recognized by the agency and it is noteworthy that the AAN was one of only two specialty societies invited to present.

Leadership Programs Bolstered The AAN is providing additional resources to Leadership Program alumni to help them navigate during the pandemic. A recent webinar presented lessons learned from leadership during a crisis and also provided a forum for alumni to learn from one another. The Emerging Leaders Program is scheduled to present virtually its group project to the Equity, Diversity, and Inclusion Joint Coordinating Council in June.

In Memoriam Join us in remembering members of the AAN and neurology community who have perished from COVID-19: William Albert "Al" Martin, MD 

T H A NK Y O U T O O UR C O M M I T M E N T T O CU R E S PR ES EN T I N G S P O N S O R

ABOUT COMMITMENT TO CURES Commitment to Cures is the American Brain Foundation’s annual fundraising and awards gala, which raises awareness for brain diseases and disorders and celebrates game-changing advances in research. The 2020 event was held in an online, live-streaming format in alignment with the global response to COVID-19. Dr. David Dodick and Susan Schneider Williams, the chair and vice chair of the foundation, were the event’s co-hosts, and the night featured special guest appearances by honorees Jim Cramer, host of CNBC’s Mad Money, Emilia Clarke, actor, and hockey legend Sidney Crosby—each one sharing their personal connection to brain disease.

We hope you’ll join us for Commitment to Cures in April 2021 in San Francisco!

President’s Column

Academy Establishes Neurology COVID-19 Relief Fund The AAN’s leadership is keenly aware of the struggles so many of our members are experiencing due to the pandemic. While we know numerous federal and state programs have been designed to help businesses weather the economic challenges they are facing, we want to provide some financial support to our members along with all of the other education and information resources we are offering.

Consequently, I am pleased to announce the AAN Institute Board of Directors has approved formation of a Neurology COVID-19 Relief Fund to assist our colleagues in the neurologic community. We have created a work group, comprised of volunteer physician leaders from various practice settings and locations, to review applications and make impartial decisions regarding hardship support grants for individuals and practices impacted by COVID-19.

The Neurology COVID-19 Relief Fund will provide grants to any neurology professional or neurology practice experiencing acute hardship and distress as an immediate result of this crisis, to enable neurologists and neurology practices to continue to provide needed health care services in communities that have become distressed as a result of the pandemic. You can find more information and apply at AAN.com.

The Academy will start the fund with $100,000, and an additional $150,000 will be available through matched donations, for a total potential contribution of $250,000. We plan to reach out to the Industry Roundtable, our partners in providing care, to secure additional funds. The goal is to secure $1,000,000 for the fund.

You will recall the AAN created a similar hardship fund for neurology professionals who suffered through the tragic hurricanes of 2017. We know this made a difference to many neurologists, residents, and medical students—and, through them, their patients, families, and communities. The experience and success of that effort gives us great confidence that the Neurology COVID-19 Relief Fund will proceed according to plan and help answer real needs among the neurologic community.

Nonetheless, we recognize the scope of the pandemic is vast and that this fund cannot address everyone’s hardship, but it’s imperative that the Academy makes the effort to offer relief to those we can. For all, the AAN will continue to advocate for fair reimbursement. We have been successful in convincing CMS to rule in favor of payment parity for phone visits, and

we are working to normalize the growth of teleneurology that has been hastened by the pandemic (for more on this, see the Capitol Hill Report on page 31).

While we are focused on the needs of neurology professionals, we also are addressing safety issues for our Stevens volunteer leaders and staff regarding the spread of the coronavirus. The Academy’s staff will continue telecommuting until at least September 8. Likewise, meetings of committees, subcommittees, work groups, and staff will be conducted by teleconferencing or video conferencing as we also restrict related travel until September. While nothing beats face-to-face interaction, our volunteer members and staff have acclimated to the “new normal” quite well and the processes of the Academy have successfully continued uninterrupted.

Again, I urge you to stay connected to the AAN through this difficult time. If you need financial assistance, please apply to the Neurology COVID-19 Relief Fund in June when it is launched. If you need expert information and resources, visit the COVID-19 Neurology Resource Center at AAN.com, and watch for our weekly COVID-19 Digest email. Please feel free to contact me if you have any concerns or ideas you wish to share.

Your Academy is here to help.

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

COVID-19 Relief Fund

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AANnews • June 2020

Education & Research

New Neurology Question of the Day Mobile App Now Available The AAN’s newest eLearning mobile application is now available.

Designed to promote continuous learning and knowledge retention with minimal effort, the Neurology Question of the Day mobile app features one new multiple-choice question each day to help members stay knowledgeable, assess their strengths and areas of weakness, and gain suggestions for resources for further study.

The app is available free to all AAN members and awards self-assessment CME upon successful completion of 25 questions. Visit AAN.com/QODapp to download the app for iOS and Android; once downloaded, simply log in with your AAN Member ID and password to begin testing your knowledge and earning CME.

FREE

education mobile app for AAN members

A separate track of questions is available for medical students, with focus on anatomy, genetics, and a wide variety of clinical topics. 

Neurology Question of the Day MEM: 17 Membership Continuum Ad—Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

FREE FOR AAN MEMBERS Due to a generous grant by the American Board of Psychiatry and Neurology, all AAN members can now enjoy free access through spring 2021.

■ 500+ hours of presentations from the 2019 Annual Meeting ■ 200+ programs and syllabi ■ Up to 242.75 AMA PRA Category 1™ CME Credits

Learn more at AAN.com/19AMOD

Education President’s&Column Research

Continuum Explores Neurology of Systemic Disease and Coding for Telehealth The new issue of Continuum: Lifelong Learning in Neurology ® provides readers with the latest information on the neurology of systemic disease. Guest editor for the issue is Joseph E. Safdieh, MD, FAAN. Topics include: Cardiac and Pulmonary Disorders and the Nervous System / Natalie R. Weathered, MD, MS Gastrointestinal Disorders and the Nervous System / Halina White, BM BCh, MA, MRCP Rheumatologic Disorders and the Nervous System / Pantelis P. Pavlakis, MD, PhD Obstetric and Gynecologic Disorders and the Nervous System / Mary Angela O’Neal, MD Electrolyte Disorders and the Nervous System / Nuri Jacoby, MD Blood Cell Disorders and the Nervous System / Alexander E. Merkler, MD Critical Medical Illness and the Nervous System / Matthew B. Maas, MD, MS, FAAN Sarcoidosis and the Nervous System / Siddharama Pawate, MD Commonly Used Drugs for Medical Illness and the Nervous System / Mary L. Vo, MD, PharmD CESC: 20 NeuroByte_Online Learning Ad—Half Page Horizontal> AN Placed in AANnews Anticancer Drugs and the Nervous System / 8.25 x 5.25 +0.125 bleed, 4C Bianca D. Santomasso, MD, PhD

Drugs of Abuse and the Nervous System / Derek Stitt, MD; Neeraj Kumar, MD This issue also includes a coding article published online ahead of print, Coding in Safdieh the World of COVID-19: Non–Face-to-face Evaluation and Management Care, by Bruce H. Cohen, MD, FAAN; Neil A. Busis, MD, FAAN; and Luana Ciccarelli, CPC, CRC. This article, along with an accompanying Continuum® Audio interview with Cohen and Busis, is open to all at ContinuumJournal.com.

As always, this issue includes a postreading self-assessment and test with the opportunity to earn up to 20 AMA PRA Category 1 Credits™ toward Self Assessment CME. AAN members pay only $399 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 are eligible to receive a 60-percent discount on the already low member rate for the Continuum and Continuum Audio subscription. 

AAN ONLINE LEARNING Browse a variety of online CME, self-assessment, and other learning activities to suit your wide-ranging interests and learning styles.

AAN.com/learn

Virtual Scientific Presentations Debut on New Platform through the new Science Highlights virtual abstract platform.”

Site visitors will be able to view up to 3,000 presentations, hear abstract presenters talk about their work, and engage in lively exchange with them via email. The program will be fully

searchable on areas such as topic, institution, or presenter, and include Emerging Science, 2020 scientific award winners, abstracts on health care disparities, and abstracts of distinction.

continued from cover

institutions highlighting their current residency, fellowship, or clerkship opportunities.

Added Rost, “Go ahead, give it a try— explore, learn, and have fun!” 

In addition, trainees will want to keep their eyes out for posters uploaded from

NeuroReady Offers Convenient, Comprehensive Review and Update in Neurology continued from cover

READY

Board Prep Edition

Continuing Certification Edition

The NeuroReady: Board Prep Edition features: Syllabi on the 21 most heavily weighted categories from the ABPN content outline for the initial certification exam in neurology Audio interviews from syllabi authors A practice exam made up of 250 multiple-choice questions with feedback by subspecialty area and suggestions for further reading 12 months of access and opportunity to download course materials for offline studying Visit AAN.com/NeuroReadyBP today to learn more and get started.

NeuroReady: Continuing Certification Edition features: Up to 15 Self-assessment CME Content based on the ABPN content outline for the cognitive expertise component (Part III) of Continuing Certification (CC) Syllabi covering new and updated science and therapies to bring you up-to-date Audio interviews for on-the-go listening 100 multiple-choice questions to help determine your strengths and areas for improvement Exam feedback by subspecialty areas and suggestions for further reading Performance results compared to other neurologists Visit AAN.com/NeuroReadyCC today to learn more and get started. 

Neurology ® Podcast: PODCAST

20 Minutes Pack a Punch!

Subscribe and download the latest podcast at Neurology.org/podcast

AANnews • June 2020 9

Conferences & Community

Why Are YOU #NeurologyProud?

Join the conversation and tell us why you’re #NeurologyProud— and proud to call the AAN your home. 

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AANnews • June 2020

AAN Staff Video Shares Appreciation of Members’ Efforts Even as they work from home, the leadership and staff of the AAN banded together to create a heartfelt “thank you” video for all of the work our members are doing during this challenging time. The video can be viewed at AAN.com/ThankYou. “We want members to know that you are in our thoughts every day as we work to support you through this difficult time,” said Chief Executive Officer Mary E. Post, MBA, CAE. “All of us are proud to be associated with the wonderful field of neurology and are inspired by your selfless commitment to bring the best possible care to patients.” 

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

CONTRAINDICATIONS TECFIDERA® (dimethyl fumarate) is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema.

WARNINGS AND PRECAUTIONS Anaphylaxis and Angioedema • TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema Progressive Multifocal Leukoencephalopathy (PML) • PML has occurred in patients with MS treated with TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received TECFIDERA for 4 years while enrolled in a clinical trial • PML has occurred in the postmarketing setting in the presence of lymphopenia (<0.9 x 109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8 x 109/L persisting for more than 6 months • At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes • Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs 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

©2020 Biogen. All rights reserved. 02/20 TEC-US-3189 v6

Herpes Zoster and Other Serious Opportunistic Infections • Serious cases of herpes zoster have occurred with TECFIDERA, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on TECFIDERA for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered • Other serious opportunistic infections have occurred with TECFIDERA, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment • Consider withholding TECFIDERA treatment in patients with herpes zoster or other serious infections until the infection has resolved Lymphopenia • TECFIDERA may decrease lymphocyte counts. In the MS placebo-controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with TECFIDERA or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 109/L or ≤0.5 x 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years) • In controlled and uncontrolled clinical trials with TECFIDERA, 2% of patients experienced lymphocyte counts <0.5 x 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. TECFIDERA has not been studied in patients with preexisting low lymphocyte counts

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–August 9, 2019).

>425,000

people have been treated with TECFIDERA worldwide 2

This includes clinical trial use and patients prescribed TECFIDERA

>810,000

global patient-years of experience 2

This includes clinical trial use and patients prescribed TECFIDERA

>12 Years IMPORTANT SAFETY INFORMATION (cont’d)

WARNINGS AND PRECAUTIONS (cont’d) Lymphopenia (cont’d) • Obtain a CBC, including lymphocyte count, before initiating treatment with TECFIDERA, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if TECFIDERA is discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution Liver Injury • Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients • Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials • Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating TECFIDERA and during treatment, as clinically indicated. Discontinue TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected Flushing • TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). Forty percent 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 (up to 325mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing

of combined clinical trial and real-world experience 1,2

ADVERSE REACTIONS

• The most common adverse reactions (incidence ≥10% and ≥2% more than

placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea

• Gastrointestinal adverse reactions: TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA • Hepatic transaminases: An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels <3 times the upper limit of normal (ULN) during controlled trials. There were no elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with TECFIDERA or placebo • Eosinophilia adverse reactions: A transient increase in mean eosinophil counts was seen during the first two months PREGNANCY • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-866-810-1462 or visiting www.tecfiderapregnancyregistry.com

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

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 RelapsingRemitting MS 3; CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis 4; 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(12):1098-1107.

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 MRI findings may be apparent before clinical signs or symptoms.

Brief Summary of full Prescribing Information 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 1 INDICATIONS AND USAGE symptoms specific to PML, have been reported in patients treated with TECFIDERA is indicated for the treatment of relapsing forms of other MS medications associated with PML. Many of these patients multiple sclerosis (MS), to include clinically isolated syndrome, subsequently became symptomatic with PML. Therefore, monitoring relapsing-remitting disease, and active secondary progressive with MRI for signs that may be consistent with PML may be useful, and disease, in adults. any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and 2 DOSAGE AND ADMINISTRATION morbidity have been reported following discontinuation of another MS 2.1 Dosing Information medication associated with PML in patients with PML who were initially The starting dose for TECFIDERA is 120 mg twice a day orally. After 7 asymptomatic compared to patients with PML who had characteristic days, the dose should be increased to the maintenance dose of 240 mg twice a day orally. Temporary dose reductions to 120 mg twice a day clinical signs and symptoms at diagnosis. It is not known whether may be considered for individuals who do not tolerate the maintenance these differences are due to early detection and discontinuation of MS dose. Within 4 weeks, the recommended dose of 240 mg twice a treatment or due to differences in disease in these patients. day should be resumed. Discontinuation of TECFIDERA should be considered for patients unable to tolerate return to the maintenance dose. The incidence of flushing may be reduced by administration of TECFIDERA with food. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Clinical Pharmacology (12.3)].

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

2.2 Blood Tests Prior to Initiation of Therapy Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of therapy [see Warnings and Precautions (5.4)].

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with TECFIDERA [see Warnings and Precautions (5.5)].

5.3 Herpes Zoster and Other Serious Opportunistic Infections Serious cases of herpes zoster have occurred with TECFIDERA, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis.

These events may occur at any time during treatment. Monitor patients on TECFIDERA for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered.

Other serious opportunistic infections have occurred with TECFIDERA, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment.

Consider withholding TECFIDERA treatment in patients with herpes zoster or other serious infections until the infection has resolved [see Adverse Reactions (6.2)].

3 DOSAGE FORMS AND STRENGTHS TECFIDERA is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a 5.4 Lymphopenia green body, printed with “BG-12 240 mg” in black ink on the body.

TECFIDERA may decrease lymphocyte counts. In the MS placebo 4 CONTRAINDICATIONS controlled trials, mean lymphocyte counts decreased by approximately TECFIDERA is contraindicated in patients with known hypersensitivity 30% during the first year of treatment with TECFIDERA and then to dimethyl fumarate or to any of the excipients of TECFIDERA. remained stable. Four weeks after stopping TECFIDERA, mean Reactions have included anaphylaxis and angioedema [see Warnings lymphocyte counts increased but did not return to baseline. Six percent and Precautions (5.1)].

(6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L). The 5 WARNINGS AND PRECAUTIONS incidence of infections (60% vs 58%) and serious infections (2% vs 2%) 5.1 Anaphylaxis and Angioedema was similar in patients treated with TECFIDERA or placebo, respectively.

TECFIDERA can cause anaphylaxis and angioedema after the first There was no increased incidence of serious infections observed in dose or at any time during treatment. Signs and symptoms have patients with lymphocyte counts <0.8x109/L or ≤0.5x109/L in controlled included difficulty breathing, urticaria, and swelling of the throat and trials, although one patient in an extension study developed PML in the tongue. Patients should be instructed to discontinue TECFIDERA setting of prolonged lymphopenia (lymphocyte counts predominantly and seek immediate medical care should they experience signs and <0.5x109/L for 3.5 years) [see Warnings and Precautions (5.2)]. symptoms of anaphylaxis or angioedema.

In controlled and uncontrolled clinical trials, 2% of patients experienced 5.2 Progressive Multifocal Leukoencephalopathy lymphocyte counts <0.5 x 109/L for at least six months, and in this group Progressive multifocal leukoencephalopathy (PML) has occurred in the majority of lymphocyte counts remained <0.5x109/L with continued patients with MS treated with TECFIDERA. PML is an opportunistic viral therapy. TECFIDERA has not been studied in patients with pre-existing infection of the brain caused by the JC virus (JCV) that typically only low lymphocyte counts. occurs in patients who are immunocompromised, and that usually leads Obtain a CBC, including lymphocyte count, before initiating treatment to death or severe disability. A fatal case of PML occurred in a patient with TECFIDERA, 6 months after starting treatment, and then every 6 to who received TECFIDERA for 4 years while enrolled in a clinical trial. 12 months thereafter, and as clinically indicated. Consider interruption During the clinical trial, the patient experienced prolonged lymphopenia of TECFIDERA in patients with lymphocyte counts less than 0.5 x 109/L (lymphocyte counts predominantly <0.5x109/L for 3.5 years) while taking persisting for more than six months. Given the potential for delayed TECFIDERA [see Warnings and Precautions (5.4)]. The patient had no recovery of lymphocyte counts, continue to obtain lymphocyte counts other identified systemic medical conditions resulting in compromised until their recovery if TECFIDERA is discontinued or interrupted due to immune system function and had not previously been treated with lymphopenia. Consider withholding treatment from patients with serious natalizumab, which has a known association with PML. The patient infections until resolution. Decisions about whether or not to restart was also not taking any immunosuppressive or immunomodulatory TECFIDERA should be individualized based on clinical circumstances. medications concomitantly.

5.5 Liver Injury PML has also occurred in the postmarketing setting in the presence of Clinically significant cases of liver injury have been reported in patients lymphopenia (<0.9x109/L). While the role of lymphopenia in these cases treated with TECFIDERA in the postmarketing setting. The onset has is uncertain, the PML cases have occurred predominantly in patients ranged from a few days to several months after initiation of treatment with lymphocyte counts <0.8x109/L persisting for more than 6 months. with TECFIDERA. Signs and symptoms of liver injury, including elevation At the first sign or symptom suggestive of PML, withhold TECFIDERA of serum aminotransferases to greater than 5-fold the upper limit of and perform an appropriate diagnostic evaluation. Typical symptoms normal and elevation of total bilirubin to greater than 2-fold the upper associated with PML are diverse, progress over days to weeks, and limit of normal have been observed. These abnormalities resolved upon include progressive weakness on one side of the body or clumsiness treatment discontinuation. Some cases required hospitalization. None of limbs, disturbance of vision, and changes in thinking, memory, and of the reported cases resulted in liver failure, liver transplant, or death. orientation leading to confusion and personality changes.

However, the combination of new serum aminotransferase elevations

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

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

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

5.6 Flushing TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/ or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing.

Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Dosing and Administration (2.1) and Clinical Pharmacology (12.3)].

Gastrointestinal TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA. Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels <3 times the upper limit of normal (ULN) during controlled trials. Elevations of alanine aminotransferase and aspartate aminotransferase to ≥3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with TECFIDERA or placebo.

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

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

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in labeling: • Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)].

• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)].

• Herpes Zoster and Other Serious Opportunistic Infections [see Warnings and Precautions (5.3)].

8 USE IN SPECIFIC POPULATIONS • Lymphopenia [see Warnings and Precautions (5.4)].

8.1 Pregnancy • Liver Injury [see Warnings and Precautions (5.5)].

Pregnancy Exposure Registry • Flushing [see Warnings and Precautions (5.6)].

There is a pregnancy exposure registry that monitors pregnancy 6.1 Clinical Trials Experience outcomes in women exposed to TECFIDERA during pregnancy.

Because clinical trials are conducted under widely varying conditions, Encourage patients to enroll by calling 1-866-810-1462 or visiting adverse reaction rates observed in clinical trials of a drug cannot be www.tecfiderapregnancyregistry.com. directly compared to rates in the clinical trials of another drug and may Risk Summary not reflect the rates observed in clinical practice.

The most common adverse reactions (incidence ≥10% and ≥2% more There are no adequate data on the developmental risk associated with than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, the use of TECFIDERA in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral and nausea. function were observed when dimethyl fumarate (DMF) was administered Adverse Reactions in Placebo-Controlled Trials during pregnancy and lactation at clinically relevant doses [see Data].

In the two well-controlled studies demonstrating effectiveness, 1529 In the U.S. general population, the estimated background risk of major patients received TECFIDERA with an overall exposure of 2244 person- birth defects and miscarriage in clinically recognized pregnancies is 2-4% years [see Clinical Studies (14)]. and 15-20%, respectively. The background risk of major birth defects and The adverse reactions presented in the table below are based on safety miscarriage for the indicated population is unknown. information from 769 patients treated with TECFIDERA 240 mg twice a 8.2 Lactation day and 771 placebo-treated patients.

Risk Summary Table 1: Adverse Reactions in Study 1 and 2 reported for There are no data on the presence of DMF or MMF in human milk. The TECFIDERA 240 mg BID at ≥ 2% higher incidence than placebo effects on the breastfed infant and on milk production are unknown.

The developmental and health benefits of breastfeeding should be TECFIDERA Placebo considered along with the mother’s clinical need for TECFIDERA and any N=769 N=771 potential adverse effects on the breastfed infant from the drug or from the % % underlying maternal condition.

Flushing 40 6 8.4 Pediatric Use Abdominal pain

18

10

Safety and effectiveness in pediatric patients have not been established.

Diarrhea

14

11

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

Nausea

12

9

Vomiting

9

5

Pruritus

8

4

Rash

8

3

Albumin urine present

6

4

Erythema

5

1

Dyspepsia

5

3

Aspartate aminotransferase increased

4

2

Lymphopenia

2

<1

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Dosage Inform patients that they will be provided two strengths of TECFIDERA when starting treatment: 120 mg capsules for the 7 day starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily. Inform patients to swallow TECFIDERA capsules whole and intact.

Inform patients to not crush, chew, or sprinkle capsule contents on food.

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

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

Progressive Multifocal Leukoencephalopathy Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received TECFIDERA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes [see Warnings and Precautions (5.2)].

Herpes Zoster and Other Serious Opportunistic Infections Inform patients that herpes zoster and other serious opportunistic infections have occurred in patients who received TECFIDERA. Instruct the patient of the importance of contacting their doctor if they develop any signs or symptoms associated with herpes zoster or other serious opportunistic infections [see Warnings and Precautions (5.3)].

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 (5.4), 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 (5.5)].

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

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

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

41347-11 Manufactured for: Biogen Inc. Cambridge, MA 02142 TECFIDERA is a registered trademark of Biogen. Š Biogen 2013 - 2019

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Conferences & Community

Transforming Leaders Program Helps Graduate See Herself as Part of Bigger Picture Often, in both work and life, the benefits of concentrating on the big picture—the most important facts about a situation and the effects of that situation on other things—rather than getting bogged down and distracted by details, is not a new concept. But acknowledging the concept and actually applying it to one’s life and career is a whole different story. For AAN Transforming Leaders Program graduate Aiesha Ahmed, MD, honing the ability to see herself as part of a larger whole and not focus simply on her role proved a career-altering revelation.

“In our initial session, our coach, Barbara Hoese, talked about Systems Thinking. I believe it was a perfect introduction to help us develop the critical thinking necessary to see ourselves as part of larger systems—at the macro economical level—and not focus on just our roles within our divisions, departments, and organizations,” said Ahmed.

A key component of the Transforming Leaders Program is the one-on-one mentoring, and “program leaders went to great lengths to find the right mentor for me,” said Ahmed. “As I was looking to develop and refine my Systems Thinking approach, I wanted to have a mentor who practiced that on a daily basis.

I was very fortunate to benefit from the mentorship of Dr. John Mazziotta, who is the Vice Chancellor of UCLA Health Sciences and CEO of UCLA Health. He took time to talk to me on a regular basis and introduced me to his core team of administrative leaders. Talking to him and meeting his team helped me understand how different organizations are structured, what traits are valuable in a team, what are the core strengths of a leader, and how successful teams decide on their strategic direction in an ever changing/evolving health care landscape.”

It didn’t take long for Ahmed to realize how her newfound perspective could be used as a tool to apply to any setting for problem solving and process improvement. “I immediately started seeing myself not only as a neurologist dealing with problems specific to my practice, but also broadly at a national level,” explained Ahmed. “This allowed me to appreciate the purpose and value of a national organization like the AAN and the need for me/us to be engaged.”

As neurologists are seeing an increase in chronic neurologic diseases due to an Ahmed aging population, Ahmed now “thinks more and more about care delivery in the form of preventive care or population-based models focused on long-term management instead of acute interventions,” adding “I’m interested in aligning value for all stakeholders and the Systems Thinking has changed the way I define and see stakeholders.”

Through her new Systems Thinking, Ahmed also learned to recognize that her desire for professional growth necessitated exploring options outside of the traditional academic department at Penn State Health in Hershey, PA, where she had been for 10 years. “So, I’m starting my next chapter as the chief of neuroscience at Spectrum Health in Grand Rapids, MI,” she relayed with great enthusiasm, crediting her mentor, Mazziotta, with being “a great sounding board for me as I explored multiple career opportunities for my next move and finally made the decision to join Spectrum Health. “ Ahmed went on to explain how the Spectrum Health department is set up as multiple service lines and includes different specialties. “What’s exciting for me is that the service line setup is the perfect infrastructure to allow piloting different models of care delivery that can provide value to patients, as well as the health care system,” she said. “The care delivery is approached from symptom/disease standpoint allowing specialists from different training background such as neurology, neurosurgery, physiatry, and pain management to work together cohesively. I believe these types of models can help us understand and plan for cost efficiency while improving quality and providing value, so I hope to contribute as part of the Spectrum Health team that focuses on this mission.”

Ahmed’s passion for care delivery doesn’t end there. The Academy also benefits greatly from her drive and knowledge through her involvement in the AAN’s Care Delivery Subcommittee, which is a subcommittee of the Medical Economics and Practice Committee.

The Transforming Leaders Program was created for innovative leaders with aspirations to transform their practice community and field of neurology, and to help turn those aspirations into reality through executive-level coaching and a fully customized intensive leadership development training program.

For more information, visit AAN.com/view/TLP. 

18

AANnews • June 2020

Tools & Resources

AAN Offers Ethical Guidance Regarding Patients and COVID-19 Pandemic continued from cover developed by the Ethics, Law, and Humanities Committee, a joint committee of the American Academy of Neurology, American Neurological Association, and Child Neurology Society, in collaboration with the Neurocritical Care Society Ethics Committee.

The AAN position statement recommends that people with chronic neurologic disease who need to see their neurologist in non-emergency situations should be offered telehealth appointments to limit potential exposure to COVID-19. Some neurologic medications may weaken a person’s immune system, putting them at greater risk of COVID-19. For example, people taking corticosteroids or immunomodulating therapies for multiple sclerosis or myasthenia gravis may be more susceptible to COVID-19.

“People should be counseled by their neurologists on how their non-emergency neurologic condition may change their risk of hospitalization and death due to a COVID-19 infection,” said position statement author Michael A. Rubin, MD, FAAN, of UT Southwestern Medical Center in Dallas and member of the AAN’s Ethics, Law, and Humanities Committee. “Entering a hospital or clinic for a non-emergency may impose a greater risk of infection than normal, even if appropriate precautions are taken.”

For patients with neurologic disease severe enough to warrant hospitalization, such as those with stroke or epilepsy, the AAN states that neurologists must still endeavor to maintain the customary standard of care in this complex, new environment.

“Now is one of the most challenging times of our careers as neurologists,” said AAN President James C. Stevens, MD,

FAAN. “Clinics and hospitals are adapting to caring for the most ill, managing scarce resources, and trying to protect people without the disease. As neurologists, we must continue to adapt our daily practice, continue to care for our most ill neurology patients, and help contribute to the care of those afflicted with COVID-19.”

The AAN also recommends that neurologists work with their patients to complete advance care planning documents.

“In the event that hospitals have to triage limited resources, it’s possible that people with advanced neurologic disease may not be offered certain elements of lifesaving care, such as ventilators and ICU beds,” said Rubin. “To ensure more control in the treatments they receive, people with advanced disease and their loved ones should discuss with their neurologist how reduced resources may impact their care and communicate their care preferences if they were to become seriously ill.”

When resources are scarce, the position statement lists criteria that should be considered when determining how those resources should be allocated, noting that decisions should be based on need, prospect of benefit, best medical evidence, and the balance of personal freedoms with the interests of the entire community, with the main goal being to maximize the number of lives saved. 

Brain & Life Helps Readers Cope with COVID-19 As people continue to reckon with the global pandemic, this month’s issue of Brain & Life® is devoted to COVID-19, starting with the cover story on how patients’ experiences in hospitals have changed and what neurologists and other health care workers are doing to treat patients and keep them safe during this critical time.

The second feature is about anxiety— both as a symptom of many neurologic conditions and a byproduct of living through a pandemic—and how to manage it, especially during a national crisis.

In the Caregiving department, caregivers of patients with dementia share the special challenges they face in trying to keep their loved ones safe and healthy and dealing with potential isolation.

Telehealth is explained in the Treatment department and how patients can prepare

to make each visit as productive as possible.

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! 

5

J U N E/J

Ways to Manage Anxiety

U LY 2 0 2 0

Telehealth Make the Most of Virtual Vis a it

Nutrition Diet Is Ke During y COVID-19

Exercise 8 Ways Stay Activto e at Home

COVID-19 H eroes We salut e health care worke Dr. James rs like ne Conners urologist on the fro nt lines of care.

AANnews • June 2020 19

Tools & Resources

Strong Results Shown in 2019 MIPS Submission Summary One of the many benefits of the Axon Registry ® is providing AAN members a solution for submitting Merit-based Incentive Payment System (MIPS) reporting to the Centers for Medicare & Medicaid Services (CMS). The 2019 MIPS submission period ended on April 30, 2020, after a one-month extension due to the COVID-19 pandemic.

During the 2019 MIPS submission period, a total of 73 practices submitted their MIPS reporting through the Axon Registry.

Forty-two practices performed individual MIPS reporting, 33 practices performed group submission, and three practices submitted both individual and group reporting. For the first time, the Axon Registry offered group submission as a 2019 MIPS reporting option for its participants.

Listed below are the estimated average scores submitted through the Axon Registry for the 2019 submission period.

Estimated Quality score: 42.44 out of 45.00 Estimated Promoting Interoperability score: 13.37 out of 15 Estimated Improvement Activities score: 15 out of 15 Estimated total score for practices that submitted all three categories: 66.8 MIPS submission through the Axon Registry offers reporting for three out of the four components of the MIPS program. For the cost component, CMS uses Medicare claims data to calculate cost measure performance, which means clinicians and groups do not have to submit any data for this performance category.

The MIPS final score will be between 0 and 100 points. Each final score will correlate to a payment adjustment. Payment adjustments will be dependent on the overall performance of clinicians. A final MIPS score of 75 points and greater will result in a positive MIPS payment adjustment for the 2019 MIPS performance period.

There were 32 quality measures used in the quality category of MIPS reporting through the Axon Registry. These are the top six most-used quality measures for 2019 MIPS reporting via the registry:

1. Axon 17: Documentation of Current Medications in the Medical Record 2. Axon 13: Medication Prescribed for Acute Migraine Attack 3. Axon 18: Advanced Care Plan 4. Axon 16C: Falls Plan of Care 5. Axon 23: Exercise and Appropriate Physical Activity Counseling for Patients with MS 6. Axon 07: Falls Screening (aggregation of AAN disease specific falls measure) Though the MIPS quality category requires the submission of six quality measures, most submissions included more than six quality measures for benchmark creation. Quality measures with benchmarks have the potential to be worth more than three points.

To enroll or learn more about the Axon Registry, visit AAN.com/Axon. 

Are You Getting Your AANe-news?

Don’t miss the latest news headlines from your Academy! As an exclusive member benefit, you should be receiving AANe-news™ the second and fourth Wednesday of each month if your email address is on file. If not, be sure to set your email filter to accept mailer@aan.com as a friendly address. Or update your email address at AAN.com/MemberProfile.

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20

AANnews • June 2020

New Neurology: Clinical Practice Explores Screening Tools, Public Engagement During Clinical Trials The June/July issue of Neurology ® Clinical Practice offers an array of articles of interest to practicing neurologists.

“Validity of the Patient Health Questionnaire-9 in Neurologic Populations” examines evidence of the validity in using the PHQ-9, a publicly available and brief depression screening tool in neurologic populations.

“Achieving Effective Patient and Public Involvement in International Clinical Trials in Neurology” provides a guide for clinicians on the rationale, methodology, and potential benefits of patient and public engagement during clinical trials.

The commentary illustrates key features of successful public engagement in the increasingly global landscape of modern clinical trials.

In “Remote Telemedicine Evaluation of Deep Brain Stimulation Candidacy,” researchers conducted a retrospective cohort analysis that found using video telemedicine to screen patients for deep brain stimulation is feasible. The finding shows video telemedicine can improve access of care to subspecialty expertise and save patients time and money.

Neurology: Clinical Practice, published six times a year, is available in print (for US members only) and online.

Visit Neurology.org/cp for more information. 

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Policy & Guidelines

AAN Members Advocate, Educate on COVID-19 Issues AAN advocates across the country have been actively engaged in the fight against COVID-19. More than 1,400 individuals have used the AAN Advocacy Action Center to contact Congress or their state policymakers regarding COVID-19 concerns. Scores of other members involved in the Academy’s advocacy programs are helping fellow neurologists learn more about the virus, how to combat it safely, and how to stay healthy. They’re sharing their stories across social media. 

22

AANnews • June 2020

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%

of patients taking TYSABRI had no sustained physical disability progression for 12 weeks vs 71% with placebo (primary endpoint: percentage with sustained increase in disability was 17% vs 29%; p<0.001)1,2

INDICATION TYSABRI® (natalizumab) is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 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.

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 gadolinium-enhanced 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 RUS T IN 10 + Y E A R S O F E XPER IEN CE WI T H T Y S A B R I OVER

ALWAYS

APPROXIMATELY

200,000

COMMITTED TO SAFETY

NEW PATIENTS

globally 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 4

DMT=disease-modifying therapy; a202,300 patients as of August 20193; b24.3% of patients as of data on file from November 2018. 4

VISIT TimeForTYSABRI.com 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 at least 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 2. Polman CH, O’Connor PW, Havrdova E, et al; for the AFFIRM investigators.

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 3. Data on file as of September 2019, Biogen.

4. Data on file as of November 2018, Biogen. © 2019 Biogen. All rights reserved. 12/19 TYS-US-2311 v2

TYSABRI (natalizumab) injection, for intravenous use 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 should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, 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 relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML [see Warnings and Precautions (5.1)]. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk.

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.

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

<1/1,000

1-24 months 25-48 months 49-72 months

†

Anti-JCV Antibody Positive No Prior Prior Immunosuppressant Immunosuppressant Use Use <1/1,000 1/1,000 3/1,000 12/1,000 6/1,000 13/1,000

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 halflives) 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 TYSABRItreated 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:

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

General Headache Fatigue Arthralgia Chest discomfort Other hypersensitivity reactions** Acute hypersensitivity reactions** Seasonal allergy Rigors Weight increased Weight decreased Infection Urinary tract infection Lower respiratory tract infection Gastroenteritis Vaginitis* Tooth infections Herpes Tonsillitis Psychiatric Depression Musculoskeletal/Connective Tissue Disorders Pain in extremity Muscle cramp Joint swelling Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test Skin Rash Dermatitis Pruritus Night sweats Menstrual Disorders* Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst Neurologic Disorders Vertigo Somnolence Renal and Urinary Disorders Urinary urgency/frequency Urinary incontinence Injury Limb injury NOS Skin laceration Thermal burn

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2

5 <1

9 4

7 3

3 2 1

2 <1 <1

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

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

Table 3:

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

General Headache Fatigue Arthralgia Influenza-like illness Acute hypersensitivity reactions Tremor Infection Upper respiratory tract infection Vaginal infections** Viral infection Urinary tract infection Respiratory Pharyngolaryngeal pain Cough Gastrointestinal Nausea Dyspepsia Constipation Flatulence Aphthous stomatitis Skin Rash Dry skin Menstrual Disorder Dysmenorrhea**

TYSABRI n=983 %

Placebo n=431 %

32 10 8 5 2 1

23 8 6 4 <1 <1

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

6 1

4 0

2

<1

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

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

General Headache Influenza-like illness Peripheral edema Toothache Infection Influenza Sinusitis Vaginal infections** Viral infection Respiratory Cough Gastrointestinal Lower abdominal pain Musculoskeletal and Connective Tissue Back pain Menstrual Disorder Dysmenorrhea**

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

*Occurred at an incidence of at least 2% higher in TYSABRI-treated patients than placebotreated patients. **Percentage based on female patients only.

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 TYSABRItreated 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 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 TYSABRI-treated 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 placebotreated 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 antibody-positivity 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 placebo-controlled studies. Approximately 10% of patients were found to have antinatalizumab 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, natalizumab-related 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)].

TYSABRI (natalizumab) Manufactured by: Biogen Inc. Cambridge, MA 02142 USA US License No. 1697 © 2015-2019 Biogen Inc. All rights reserved.

08/2019 U.S. Patent Numbers: 5,840,299; 6,602,503

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.

Telemedicine Has Proven Its Value Past Current Crisis Member Perspective by Elaine C. Jones, MD, FAAN, AAN Board Member In this time of the COVID-19 pandemic, many things have been put on hold, but dramatic and rapid changes have taken place in the way we practice neurology and maintain distancing to protect ourselves, our staff, and our patients. Most notable is the rapid implementation of telemedicine services and the AAN has been at the forefront of helping with this process. However, what happens when the crisis is over? Do we go back to health care as usual? At the AAN, we don’t think this is the right future and are actively working to assure that appropriate telemedicine services can continue. My current work as a teleneurologist with a large, national telemedicine company has given me great experience with the process even prior to the pandemic. Before this job, I ran my own solo, private practice in Rhode Island and so I understand the needs and struggles of a business.

I currently chair the AAN’s Coding and Payment Policy Subcommittee and sit on the Board. These roles have given me novel insight into many aspects of the current environment.

Even prior to the pandemic, the AAN was working on a telemedicine policy to define the uses, legislative and regulatory issues, licensure and liability issues, and coding and payment issues. From webinars to NeuroBytes to FAQs all about the implementation, examination techniques, and pros and cons of telemedicine, AAN members have access to all the resources they need on our website.

But now as this wave of the pandemic seems to be slowing in some areas and everyone is starting to think about opening up safely, the AAN is already hard at work talking to legislators, regulators, and payers to allow the continued use of telemedicine. We strongly feel that our patient population lends itself to the use of ongoing remote monitoring and care. For elderly, low mobility, or chronically ill patients, the use of remote care can lead to better access to care. We understand some patients can’t travel well or for long distances, and that disabled or low income patients can’t afford the time away from work, and others just need to be monitored more closely at times but not necessarily by coming into the office. The use

Jones of telemedicine in concert with interspersed face-to-face visits could improve care for these patients and therefore needs to be available and appropriately compensated for even after the pandemic has ended. We continue to interact with regulators at CMS and provide comments on proposed policies for this year and 2021. We are in discussions with private payers (BCBS, UHC, and Cigna) to work with them on similar coverage policies.

I encourage you to check out the AAN website for current and ongoing resources. We also would like to hear from you with any challenges as well as your experiences with using remote care in your practice (practice@aan.com). Many neurologists already had experience with telemedicine in the setting of stroke care and we have been able to lead the way in appropriately using this technology in other settings.

These are challenging times but the AAN is hard at work to support members and their patients so we can all continue to provide the best care and maintain successful businesses into the future.

AAN Advocacy Victory: CMS Announces Payment Parity for Phone Visits during the PHE On April 30, the Centers for Medicare & Medicaid Services (CMS) issued additional rulemaking in response to COVID-19.

As part of the rulemaking, CMS announced that it would pay for telephone visits at parity with similar E/M visits during the public health emergency (PHE). The changes are retroactive to March 1 and the telephone codes are distinct from the coding that is used for video visits. The codes for telephone visits are 99441-99443 and they are now being paid at the same level as those for similar established patient E/M services (99212-99214) during the PHE. This follows CMS’ initial decision to begin to pay for telephone services during the PHE and would increase payments for these services from a range of about $14–$41 to about $46–$110. The AAN advocated for this change in our communications both with Congress and CMS. 

AANnews • June 2020 31

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