2019 September AANnews

VOLUME 33 · ISSUE 9 · September 2019

UNDER THE MICROSCOPE: 2020 MEDICARE PROPOSED FEE SCHEDULE Read President Stevens' Response, Page 4 The Centers for Medicare & Medicaid Services (CMS) issued on July 29 a proposed rule that includes proposals to update payment policies, payment rates, and quality provisions for services furnished under the Medicare Physician Fee Schedule on or after January 1, 2020.

The proposed rule illustrates the importance of the AAN’s regulatory advocacy efforts on behalf of neurologists and their patients. Below are key changes that would affect neurology.

Evaluation and Management (E/M) CMS is proposing to make significant changes beginning in 2021 to policies related to outpatient evaluation and management (E/M) coding, leading to substantial payment increases for neurology.

CMS is proposing to withdraw its plan to collapse the existing levels of E/M coding.

Instead, CMS plans to implement revised E/M documentation guidelines as laid out by the American Medical Association (AMA) CPT Editorial Panel.

It maintains the existing five levels of coding for established patients and reduces the number of levels for new patients to four by eliminating 99201.

Continued on page 9

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2020 Annual Meeting Abstract Submission Opens this Month

Webinar Removes Mysteries of Stroke Management Technologies

Your breakthrough research could be seen by neurologists, neuroscientists, and researchers from more than 100 countries if your abstract is selected for presentation at the 2020 AAN Annual Meeting, to be held in Toronto, Canada, April 25 through May 1.

In recent years, there have been many advances that have made stroke care easier for you and your patients—most notably, the expansion of telestroke. This webinar will cover the basics of telestroke, letting you know how to code, how to treat telestroke patients, and what laws you must know to practice remote care. Other technological advances will be addressed, like routing and triage and using APPs in stroke care, to assist in improved practice management.

Online abstract submission opens September 3 at AAN.com/view/20Abstracts and submissions are due by no later than 11:59 p.m. CT on October 21.

Continued on page 20

5 Meet Your New Board

Member: Lyell K. Jones, Jr., MD, FAAN

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17 AAN Publishes New Guideline Update on Immunization in MS

Continued on page 8

26 2020 AAN Award

Applications Now Open

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In Multiple

Sclerosis —

GREY MATTERS, TOO

Learn more about Multiple Sclerosis at MSBrainPreservation.com/art © 2019 Celgene Corporation All rights reserved. 04/19 US-CLG-19-0571

AANnews · September 2019

CONTENTS

News Briefs

Cover Under the Microscope: 2020 Medicare Proposed Fee Schedule 2020 Annual Meeting Abstract Submission Opens this Month Webinar Removes Mysteries of Stroke Management Technologies President’s Column 2020 Proposed Physician Fee Schedule: Victory on E/M, Work to Do on EEG · · · · · · · · 4 Meet Your New Board Member Lyell K. Jones, Jr., MD, FAAN · · · · · · · · · · · · · 5 Tools & Resources Understanding How You Get Paid: Part 3 · · · · · · · · · · · · · 6 Exploring the Other Side of the QPP: Alternative Payment Model Resources · · · · · · · · · 7 AAN Award Recognizes Innovation in Quality and Axon Registry Data Use · · · · · · · · · 7 Growing Practice Support Network Welcomes Your Questions · · · · · · · · · · · · · · 8 Policy & Guidelines AAN Publishes New Guideline Update on Immunization in MS · · · · · · · 17

Capitol Hill Report · · · · · · · · 19 Conferences & Community Save $100 on Fall Conference and New Advanced Practice Provider Pre-conference Before September 12 · · · · · · 20 Apply for Free FAAN Status, Set Yourself Apart Within the Academy · · · · · · · · · · · 20 Brainstorm Competition Helps Propel Winner’s Breakthrough Work Forward · · · · · · · · · · · · · · 21 Do You Have an Innovative Idea You Want to Share? · · · · 21 Education & Research October 1 Is Last Chance to Apply for 2020 Research Program Opportunities · · · · · 22 American Brain Foundation Mentored by Raymond Adams? Honor His Legacy and Support the Next Generation of Neurologists · · · · · · · · · · · ·25 2020 AAN Award Applications Now Open · · · · · 26 Careers · · · · · · · · · · · · · · · ·27 Dates & Deadlines · · · · · · · · · 28

Explore New AAN and AHS Guidelines on Treating Pediatric Migraine · · · · · · · · 19

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

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

Contact Information

For advertising rates, contact:

American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415

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

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

memberservices@aan.com

Website: AAN.com

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

New Work Groups Have Academic Focus As part of its ongoing commitment to support academic neurologists across their professional lifetimes and address the current and future needs of academic neurology departments, the AAN has created two new work groups. The Advancing Women in Academics Work Group, with Chair Janice M. Massey, MD, FAAN, and Vice Chair and AAN President Elect Orly Avitzur, MD, MBA, FAAN, will investigate issues women face as they seek advancement in academic medicine and explore ways to mitigate these issues. The Academic Business Administrator Work Group, chaired by Jane Czech, MS, MBA, of UCSF, will look at the needs of academic business administrators and identify a business administrator curriculum for the 2020 Annual Meeting. The work groups were formed following the Neurology Department Chair and Academic Business Administrator Summit in March.

Publication Accepted for MEDLINE, PubMed The AAN’s publication Neurology® Neuroimmunology & Neuroinflammation has been reviewed and accepted for inclusion in MEDLINE by the US National Library of Medicine (NLM). MEDLINE citations are indexed with NLM medical subject headings and other metadata and are searchable in PubMed. To learn more, visit PubMed or the Neurology website at https://nn.neurology.org. 

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

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.

President’s Column

2020 Proposed Physician Fee Schedule: Victory on E/M, Work to Do on EEG At the end of July, the Centers for Medicare & Medicaid Services published its proposed 2020 Medicare Physician Fee Schedule. Member volunteers and staff immediately examined the proposal for any new developments or changes that would affect our members and patients. You can read an analysis of the proposed changes and possible impact on neurology on the front page of this issue.

Stevens

Most notably, the AAN had a significant win on the topic of evaluation and management (E/M) codes! If you recall last year, CMS proposed changes in this area that would have collapsed payment and adversely affected compensation for your hard work. The Academy and similarly minded organizations fought hard against those changes and CMS relented, pushing them off to 2021.

Well, now CMS has essentially backed off this plan altogether in the proposed fee schedule for next year! Not only that, but it proposes substantial reimbursement increases to outpatient E/M services coming in 2021, as well as simplified documentation guidelines. Our member leaders and staff put great effort into this, meeting with CMS officials and sharing our views through numerous letters and conversations. Their hard work has paid off—and has been duly recognized as you’ll read below.

On the other hand, CMS proposed payments for a new coding structure for reporting long-term EEG monitoring services to go into effect next year. These changes could result in reduced compensation for neurologists, and we have marshalled our forces to fight this.

Yet, there’s good news in other areas of the proposal, most notably new and enhanced care management services that recognize the additional care provided to complex patients. CMS has even created two new codes for Principal Care Management.

Also, there are new Quality Payment Program policies to update and realign aspects of the Merit-based Incentive Payment System (MIPS) and Alternative Payment Models (APMs) and lessen some administrative burdens for participants.

We have thanked CMS for responding positively to our concerns about E/M codes and regulatory burden, and we are submitting our objections to the proposed EEG changes, working again in collaboration with the National Association of Epilepsy Centers, American Clinical Neurophysiology Society, and the American Epilepsy Society. CMS is expected to publish the final rule in November.

4

AANnews • September 2019

Last month, AANnews announced that the Academy received the Profiles of Excellence Award from the American Association of Medical Society Executives (AAMSE) for our 2018 regulatory work on pushing back the E/M code changes. AAMSE recognizes organizations for efforts that advance the field of organized medicine and improve the lives and practices of physicians and the patients they serve. The AAN was cited for its successful meetings with CMS officials, regulatory comment submissions, legislative work, patient group outreach, media coverage, and other efforts that secured wins for neurologists in the final 2019 Medicare Physician Fee Schedule.

The judge’s comments on our submission stated, “This truly was a full court press and AAN pulled it off. There were many other specialties that would have been impacted and thanks to AAN’s quick and efficient response, they will all benefit.

It's a great example of a fully integrated, holistic approach to advocacy. I like how comprehensive the plan was, working crossdepartmentally to ensure that all information is shared with the relevant people. That helped build on successes in one area to find further successes. It was clear from the application that many resources were put in place to try and change the E/M cuts. Nice to see the positive outcome.”

This is the same purposeful approach our team of volunteer members and staff are taking with the 2020 proposed fee schedule. The AAN and its leadership strive to enhance member career satisfaction, and we know that overcoming regulatory burdens and advocating for fair reimbursement are key to member satisfaction. Strengthening our profession also makes neurology more attractive to medical students and helps our pipeline concerns. I can’t promise you we’ll win every battle, but I can promise we’ll do everything possible to protect you and your patients. 

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

Meet Your New Board Member

Lyell K. Jones, Jr., MD, FAAN Lyell K. Jones, Jr., MD, FAAN, recently joined the AAN Board of Directors as an ex officio member due to his status as chair of the Quality Committee. Jones is a consultant and professor of neurology at the Mayo Clinic in Rochester, MN, where he has been a member of the consulting staff since 2009.

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

As a neurology resident, I joined the AAN’s delegation to the American Medical Association. It was a crash course in health care policy and economics, which have since become career interests. This work introduced me to the distinctive partnership between member volunteers and AAN staff: both of these groups are talented and motivated and bring different perspectives to the Academy’s work. Over time, I’ve learned that my experiences through the AAN can help me better serve my home institution, and vice versa.

Since that first position with the AAN, I’ve had the opportunity to work in medical economics, leadership development, graduate medical education, developing the Axon Registry®, and most recently helping launch the AAN’s new Quality Committee. Each step of the way, I’ve gotten more out of it than I’ve put into it.

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

Working for AAN members through committee service has been very rewarding. Serving on the Board offers an opportunity to step out of the relatively narrow focus of a committee, subcommittee, or work group, and look at the big picture of our organization, our specialty, and how we fit into a rapidly changed health care landscape. I’ve been impressed with the Board’s emphasis on strategic thinking, which is necessary to help our members continue to deliver the best possible care to their patients into the future.

The AAN is a large organization that serves an incredibly broad array of constituencies, and the common misperception that it serves the interests of “everyone but me” has been well-described in these pages. In my time with the Academy, I’ve been surprised by (and impressed with) its openness to change and willingness to listen. The AAN is a membercentric organization, and it would be unable to effectively serve its more than 36,000 members if it didn’t listen to ideas, suggestions, concerns, and innovations that those members bring forward. In the same vein, any organization that does not take the opportunity to adapt and improve will lose its way. The Academy has been courageous in its willingness to innovate in the service of its members. Investments in clinical research, wellness, advocacy, leadership development, the Axon Registry, and redesigning the Annual Meeting―all based on feedback from members―are just a few examples that come to mind.

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

There is no other organization that can so effectively represent the entirety of our diverse specialty across all domains: clinical practice, neuroscience research, neurology education, health care policy, and advocacy. The AAN is the glue that holds neurology together. Neurologists all serve patients with neurologic disease, whether it’s through direct clinical care, finding better treatments for neurologic disorders, or training the next generation of neurologists. By serving all its members, the AAN helps us work toward that shared goal. 

What experiences and viewpoints do you bring to this role?

Professionally, I’ve had the good fortune to combine patient care, neurology education, clinical research, and administrative service in my work. I have the best job in the world, and I hope to bring the better part of all these perspectives to the Board.

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

AANnews • September 2019 5

Tools & Resources

Understanding How You Get Paid: Part 3 Once a CPT code has been reviewed by the American Medical Association (AMA) for valuation, the payment rates are determined by the Centers for Medicare & Medicaid Services (CMS). Let’s continue looking at the long-term EEG monitoring code set, which the AMA Relative Value Scale Update Committee (RUC) recently reviewed and sent recommended values to CMS. The Medicare Physician Fee Schedule Proposed Rule, published by CMS in July, is the first public notice of a new code set, including the proposed payment rates. As the title implies, the rates are proposed by CMS and subject to public comment.

The final payment rates, which take effect January 1, are included in the Medicare Physician Fee Schedule Final Rule.

Each year, the AAN carefully reviews the proposed payment rates and comments in objection to negative adjustments in an effort to maximize reimbursement for neurologic care.

The new code set for long-term EEG monitoring introduces significant changes to how the services are reported including the deletion of codes 95950, 95951, 95953, and 95956 and establishment of 23 new codes. Effective January 1, 2020, there will be 10 “professional component codes” to report the work of the physician or other qualified health care professional (QHP) and 13 separate “technical component codes” to report the work of the EEG technologist.

The professional component codes consist of the physician or QHP review, analysis, interpretation, and reporting the results of a continuous recording EEG, and are differentiated by three components: 1. Length of recording being interpreted 2. EEG recording with video vs. without video 3. Timing of the physician or QHP report generation: whether diagnostic interpretations and reports are made daily or whether the professional interpretation is performed at the end of the entire recording The technical component codes consist of the technologist’s monitoring, maintenance, review of data, and creation of a technical summary of a continuous recording EEG and are also differentiated by three components:

6

AANnews • September 2019

1. Length of recording 2. EEG recording with video vs. without video 3. Level of technologist monitoring for the recording (i.e., unmonitored, intermittently monitored, or continuously monitored) CPT® is a registered trademark of the AMA. A full description of the code language and reporting guidelines is available at AAN.com/view/cpt. The 2020 payment rates for new CPT codes are published annually in November as part of the Medicare Physician Fee Schedule Final Rule. The final article in this series of AANnews coding articles will include 2020 reimbursement changes and coding guidance on how to use the new EEG code set.

Visit AAN.com/view/cpt to read the previous AANnews articles in this coding series: February 2019: The AAN’s Role in Advancing Coding and Reimbursement for Neurology May 2019: Understanding How You Get Paid: Part 1 July 2019: Understanding How You Get Paid: Part 2 

Tools & Resources

Exploring the Other Side of the QPP: Alternative Payment Model Resources As year four of the Quality Payment Program (QPP) fast approaches, neurologists and other eligible clinicians should review and understand the options they have for reporting in 2020, especially as CMS urges the shift towards Alternative Payment Models (APMs) from Merit-based Incentive Payment System (MIPS). In 2017, 16,219 neurologists and neurology-APPs reported to MIPS and maximum positive payment adjustments across the program were only 1.88 percent. Neurologists should consider APMs— the other track of the QPP—to maximize incentives and potentially minimize burden. To understand your participation status, it’s important to learn the different types of APMs that exist within this track of the QPP. Advanced Alternative Payment Models (Advanced APMs): These Medicare APMs offer an automatic five-percent incentive and exclude you from reporting MIPS. Advanced APMs must use certified EHR technology, base payments for covered services using quality measures similar to those quality measures used in MIPS, and either are part of a Medical Home Model or require bearing significant financial risk.

Examples of Advanced APMs are the Bundled Payments for Care Improvement (BPCI), Next Generation ACO Model, and Medicare Shared Savings Program (MSSP) Track 2 and 3.

MIPS APMs: This type of APM includes clinicians that are eligible in the MIPS track of the QPP. Participants in these models are held accountable for cost and quality provided to Medicare patients but are subject to special MIPS scoring under the APM scoring standard. MIPS APMs include onesided risk models that are not considered Advanced APMs. MSSP Track 1 is a MIPS APM. All-Payer/Other-Payer Advanced APMs: Clinicians that fall into this category participate in a combination of Advanced APMs and non-Medicare payment arrangements, designated

as Other-payer Advanced APMs. Other-payer Advanced APMs have similar criteria to Advanced APMs through Medicare.

Examples of Other-payer Advanced APMs include those that address the Medicaid, Medicare Advantage, and commercial or private populations.

Find out your participation status in the QPP, including whether you are considered a Qualifying APM Participant (QP), using the Participation Status Tool at QPP.cms.gov/participation-lookup.

The AAN provides you with tools and resources to help you be successful in your transition to value-based care. For timely QPP-related resources and information for neurologists, please visit AAN.com/view/macra or email macra@aan.com.

Join us for in-person and online events related to APMs soon: Friday, October 18 / AAN Fall Conference Program: Transitioning Your Practice into a Value-based Model Tuesday, November 19 / Practice Management Webinar: Seeing the Future Clearly: How to Succeed in 2020 

AAN Award Recognizes Innovation in Quality and Axon Registry Data Use Apply now for the AAN QI Innovation Award. The AAN is now accepting applications from all interested individuals. This award recognizes clinicians and/or care teams who have implemented projects designed to improve safety or quality in practice. This year the AAN Quality Committee will give out two awards with a $1,000 prize for each recipient.

One of the awards will be given to an Axon Registry ® participant practice that demonstrates the use of Axon Registry data via the registry user dashboard to drive quality improvement in practice. The other award will be given to a clinician or care team that demonstrates quality improvement in practice or increased patient safety via other data such as internal quality improvement data or data from other registries.

Applicants do not need to be AAN members and all are encouraged to apply including physicians, residents/fellows, advance practice providers, nurses, quality improvement specialists, and care teams. If you are interested in enrolling or learning more about the Axon Registry, which is a free benefit for US members, contact quality@aan.com.

You can find out more information about the QI Innovation Award and apply at AAN.com/view/QIAward. 

Dementia: Caregiver Education and Support Falls: Querying About Falls for Patients Headache: Medication Prescribed for Acute Migraine Attack Total

+

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Q4

400

300

100

75%

Q3

400

250

150

62%

Q2

400

200

200

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Q1

400

100

300

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Parkinson's: Psychiatric Symptoms Assessment ALS: End of Life Planning Assistance

AANnews • September 2019 7

Tools & Resources

Growing Practice Support Network Welcomes Your Questions With the addition of the 2019 Practice Leadership Program graduating class, the AAN’s Practice Support Network has grown to 20 members strong. The network was originally created by the 10 graduates of the 2018 leadership program class out of a desire to give back to the AAN and share their practice knowledge with and support their colleagues. That desire led to the creation of the Practice Support Network to facilitate answering member questions emailed to the practice@aan.com inbox.

As Michael Markowski, DO, FAAN, explained in the October 2018 issue of AANnews, “The 10 Practice Leadership Program graduates proposed a system to assist our fellow neurologists in practice, in particular those who may be geographically isolated or unable to take advantage of some of the AAN resources through Annual Meetings or leadership programs.

We felt this would be the best way for neurologists to support each other, in particular, our colleagues struggling with practice-related issues.”

To reach this network and their breadth of experience, email practice@aan.com. The inbox was the brainchild of the AAN’s Small and Solo Practice Task Force as a resource for members with questions about practice-related issues including MIPS/ MACRA, practice management, and coding. AAN staff monitor this inbox and respond within one business day. If the question is outside their area of expertise, they will reach out to the Practice Support Network. Questions submitted to the network

are de-identified to protect anonymity.

Markowski The network’s insights are gathered and returned to the questioner. In this way, members are free to ask about sensitive topics they would prefer not to bring out in the AAN’s public forums, such as the SynapseSM online community. 

Contact practice@aan.com if you have questions about: Coding MIPS/QPP Practice Management/Practice Efficiency

Webinar Removes Mysteries of Stroke Management Technologies continued from cover Using Technology for Better Practice Management of Stroke Mark J. Alberts, MD, FAHA; Elaine C. Jones, MD, FAAN; Lawrence R. Wechsler, MD, FAAN October 1, 2019 Register by September 30 AAN.com/view/pmw19 Learning Objectives Understand the latest research demonstrating the effectiveness of remote care for stroke patients Learn how to adhere to proper coding practices and other regulations to be a successful teleneurologist who treats stroke

8

AANnews • September 2019

Alberts

Jones

Understand the latest technologies that will assist in the improved practice management of stroke care Learn how to offer high-quality, high-value care for remote care patients suffering from stroke Know how to delegate among a care team to continue to offer patientcentered care The AAN’s practice management webinars have a new format but the

Wechsler

same game-changing expert insights!

A live, 30-minute webinar with expert faculty will be held on October 1, followed by several shorter recorded online lectures that go deeper into the topic posted the week of October 7, concluding with a 30-minute live webchat on October 29 for more Q&A. All course materials can be accessed on the new AAN online learning center at Learning.AAN.com.

Learn more and register at AAN.com/view/pmw19. 

Tools & Resources

Under the Microscope: 2020 Medicare Proposed Fee Schedule continued from cover The proposed changes will also allow clinicians to choose E/M visit levels using either medical decision making or time.

CMS is further proposing to implement an add-on code for prolonged service time and a separate add-on code to recognize the complexity inherent to E/M services that are part of ongoing care related to a patient’s single, serious, or complex chronic condition.

These changes are positive news for neurology and represent a substantial change from the code collapse that was proposed by CMS in the previous fee schedule!

AAN members and staff committed extensive resources over the past year to work with CMS and the AMA to build a new E/M structure that will meet the needs of neurologists and their patients.

The AAN commends CMS for listening to the AAN and recognizing the value of cognitive care.

Electroencephalography (EEG) Coding Changes A new coding structure for reporting long term EEG monitoring services will go into effect January 1, 2020: Deletes existing codes 95950, 95951, 95953, and 95956 Creates 10 new codes for the professional component (physician services) Creates 13 new codes for the technical component (technologist services) The AAN is conducting an in-depth analysis of the proposed payment rates to fully understand the financial impact to our members and will share detailed coding guidance in future publications as well as next steps.

The AAN, along with the National Association of Epilepsy Centers, American Clinical Neurophysiology Society, and the American Epilepsy Society, has spent the last several months actively advocating to maintain maximum reimbursement for these critical services. This included a meeting directly with CMS officials who oversee the Physician Fee Schedule.

Quality Payment Program This rule also includes proposed updates to the Quality Payment Program, which includes the Merit-based Incentive Payment System (MIPS) and Alternative Payment Model (APM) tracks.

The rule proposes increasing the performance and exceptional bonus thresholds for 2020 to 45 points and 80 points, respectively. Additionally, CMS proposes decreasing the weight of the MIPS Quality component to 40 percent from 45 percent and increasing the weight of the MIPS Cost component to 20 percent from 15 percent. There are no proposed changes to the Improvement Activities and Promoting Interoperability component weights.

CMS is proposing no changes to the MIPS low-volume threshold, indicating those clinicians deemed eligible to participate in 2019 can expect to continue next year.

The rule also introduces proposed changes to the cost measure attribution methodology for the Total Per Capita Cost and Medicare Spending Per Beneficiary measures and 10 additional episode-based measures.

Changes to Care Management Services CMS is proposing to make changes to several care management services in 2020, including increased payment for transitional care management (TCM) and eliminating billing restrictions on several codes that cannot currently be billed during the 30-day period.

The agency is proposing to adopt new codes that more accurately account for additional clinical staff time spent on chronic care management (CCM).

New codes for principal care management (PCM) services are also proposed, which account for care management associated with patients with a single high-risk disease or complex chronic condition.

The AAN commends the agency for continuing to recognize the additional care provided to complex patients that extends beyond a typical face-to-face encounter. 

The AAN is disappointed the agency’s proposed payment rates do not fully follow the recommendations of the AMA for the entire set of professional service codes and very concerned about implications of such a reduction.

We are making our objections known to CMS and working toward improving the values in the final rule.

AANnews • September 2019 9

IN PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS (RMS)

START WITH THE POWER AND EXPERIENCE OF TYSABRI

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

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

1,2

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

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

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

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

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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

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

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

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

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

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

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

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

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

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

Most patients did not interrupt treatment with TYSABRI during infections.

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

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

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

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

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

TYSABRI (natalizumab) injection, for intravenous use

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Brief Summary of Full Prescribing Information

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

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

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

1.

INDICATIONS AND USAGE

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

2.

DOSAGE AND ADMINISTRATION

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

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

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

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

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

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

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

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

4.

CONTRAINDICATIONS

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

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

5.

WARNINGS AND PRECAUTIONS

5.1. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received TYSABRI. Three factors that are known to increase the risk of PML in TYSABRI-treated patients have been identified: • Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 6 years of TYSABRI treatment.

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

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

Anti-JCV Antibody Positive Anti-JCV Antibody Negative

TYSABRI Exposure†

No Prior Immunosuppressant Use

1-24 months

<1/1,000

1/1,000

<1/1,000

25-48 months

3/1,000

12/1,000

49-72 months

6/1,000

13/1,000

Prior Immunosuppressant Use

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

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

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

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

Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom suggestive of PML. Symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold TYSABRI dosing immediately and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of TYSABRI or due to differences in disease in these patients.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 2:

Table 3:

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

TYSABRI n=627 %

Placebo n=312 %

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

38 27 19 5 5 4 3 3 2 2

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

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

Psychiatric Depression

19

16

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

16 5 2

14 3 1

Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test

11 10 5

10 9 4

Skin Rash Dermatitis Pruritus Night sweats

12 7 4 1

9 4 2 0

Menstrual Disorders* Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst

5 3 2 2

4 <1 1 <1

Neurologic Disorders Vertigo Somnolence

6 2

5 <1

Renal and Urinary Disorders Urinary urgency/frequency Urinary incontinence

9 4

7 3

Injury Limb injury NOS Skin laceration Thermal burn

3 2 1

2 <1 <1

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

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

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

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

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

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

TYSABRI n=983 %

Placebo n=431 %

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

32 10 8 5 2 1

23 8 6 4 <1 <1

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

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

Skin Rash Dry skin

6 1

4 0

Menstrual Disorder Dysmenorrhea**

2

<1

Respiratory Pharyngolaryngeal pain Cough Gastrointestinal Nausea Dyspepsia Constipation Flatulence Aphthous stomatitis

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

Table 4:

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

TYSABRI n=214 %

Placebo n=214 %

General Headache Influenza-like illness Peripheral edema Toothache

37 11 6 4

31 6 3 <1

Infection Influenza Sinusitis Vaginal infections** Viral infection

12 8 8 7

5 4 <1 3

Respiratory Cough

7

5

Gastrointestinal Lower abdominal pain

4

2

12

8

6

3

Musculoskeletal and Connective Tissue Back pain Menstrual Disorder Dysmenorrhea**

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

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

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

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

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

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

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

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

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

Anti-natalizumab antibodies were neutralizing in vitro.

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

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

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

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

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

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

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

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

Blood disorders: hemolytic anemia 8.

USE IN SPECIFIC POPULATIONS

8.1.

Pregnancy

Risk Summary There are no adequate data on the developmental risk associated with the use of TYSABRI in pregnant women. In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose. These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals [see Data].

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

Data Animal Data In developmental toxicity studies conducted in guinea pigs and monkeys, at natalizumab doses up to 30 mg/kg (7 times the recommended human dose based on body weight [mg/kg]), transplacental transfer and in utero exposure of the embryo/fetus was demonstrated in both species.

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

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

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

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

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

8.2.

Lactation

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

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

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

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

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

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

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

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

• Inform all of their physicians that they are receiving TYSABRI. • Plan to see their prescriber three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing TYSABRI. Progressive Multifocal Leukoencephalopathy Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received TYSABRI. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Instruct the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Instruct the patient that the progression of deficits usually leads to death or severe disability over weeks or months.

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

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

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

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

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

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

Full Prescribing Information is available at TYSABRIhcp.com.

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

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

Policy & Guidelines

AAN Publishes New Guideline Update on Immunization in MS The AAN published “Practice Guideline Update: Vaccine-preventable Infections and Immunization in Multiple Sclerosis,” in Neurology ® online on August 28, 2019, and in the September 24, 2019, print issue. The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

According to the updated guideline, preventing infections through vaccine use is a key part of medical care for people with multiple sclerosis (MS).

Patients who have MS should receive vaccines according to the standard vaccine guidelines. There is some evidence that vaccines do not increase risk of developing MS; for several vaccines, the authors' confidence in the evidence is low or moderate.

populations, clinicians must screen for latent infections before starting ISIM therapy even when not specifically mentioned in prescribing information and should consult specialists regarding treating patients who screen positive for latent infection.

The guideline states that there is no evidence that MS alone increases the risk of acquiring vaccine-preventable infection. Individuals with MS have at least the same risk as unvaccinated individuals without MS, although having a chronic disease may put them at greater risk of infection than the general population.

influenza and tetanus vaccines might not work well enough to prevent infection for some people with MS who take certain ISIM medications.

Read the guidelines and access summaries for clinicians and patients, a Spanish-language clinician summary, a clinical algorithm, and a slide presentation set at AAN.com. For more information, email guidelines@aan.com or call (612) 928-6069. 

Clinicians should recommend that people with MS receive the influenza vaccination Clinicians must screen for latent infection annually, unless according to prescribing information there is a specific before initiating immunosuppressive or contraindication.

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Movement Disorders August 2019, VOL. 25, NO. 4

Policy & Guidelines

Explore New AAN and AHS Guidelines on Treating Pediatric Migraine

Oskoui

Two new guidelines, “Practice Guideline Update Summary: Acute Treatment of Migraine in Children and Adolescents” and “Practice Guideline Update Summary: Pharmacologic Treatment for Pediatric Migraine Prevention,” were published in the August 14, 2019, online issue of Neurology ®. The guidelines were codeveloped by the AAN and American Headache Society (AHS).

The pediatric migraine guideline lead author, Maryam Oskoui, MD, MSc, FAAN, said the guideline update summaries report there is evidence to support the use of acute treatments for migraine in children and adolescents. However, the use of preventive treatment in children and adolescents is problematic, given scarce evidence supporting efficacy. It is important for clinicians to be familiar with the evidence-based treatments, including formulations for acute therapy for those with nausea and vomiting.

Clinicians should give children and adolescents with headache a diagnostic evaluation that includes a careful medical history and general physical and neurologic exams. They also should be taught about self-management of migraine.

Evidence-based acute treatments for migraine are available for children and adolescents. The use of preventive treatments and the lack of evidence to support their use need to be carefully weighed by the child, parent, and clinician.

Both guidelines have been endorsed by the American Academy of Pediatrics and the Child Neurology Society.

Visit AAN.com to read the guideline and access clinician summaries and presentation slide sets for each guideline and one patient summary that covers both guidelines.

For more information, email guidelines@aan.com or call (612) 928-6069. 

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

AAN Comments on Senate Drug Pricing Proposal The Senate Finance Committee recently released The Prescription Drug Pricing Reduction Act of 2019, a proposal to lower prescription drug costs for Medicare beneficiaries and the federal government and to realign perceived misincentives for Part B drugs. The AAN submitted extensive comments highlighting support for direct price negotiation, price transparency, and the proposed cap of $3,100 for out-of-pocket drug costs for Medicare patients. Congress will likely use this proposal and others as they consider legislative solutions to address drug pricing in the fall.

Victory on IRF Final Rule The Centers for Medicare & Medicaid Services (CMS) released a final rule clarifying the definition of a “rehabilitation physician” serving in inpatient rehabilitation facilities (IRFs). The AAN commented in support of the finalized definition, as it will allow for the flexibility that is required for neurologists to continue to provide high quality care in the IRF setting. This final definition represents a rejection of calls for a more restrictive definition that would have effectively precluded neurologists from serving as rehabilitation physicians within IRFs. The AAN’s advocacy was recognized by CMS leadership, who took the time to personally write a letter to the AAN responding to the AAN’s input. 

AANnews • September 2019 19

Conferences & Community

Save $100 on Fall Conference and New Advanced Practice Provider Pre-conference Before September 12 September 12 is the last chance to save $100 on registration and to book your hotel for the 2019 AAN Fall Conference, set for October 18-20 in Las Vegas, before on-site pricing goes into effect.

Advanced Practice Provider Pre-conference

The Fall Conference is poised to offer the hottest topics in the field of neurology, real-world issues in practice management, and innovative science—plus valuable end-of-year CME. Some of this year’s new programming highlights include:

A new Advanced Practice Provider Preconference is set to debut on October 17, just prior to the Fall Conference. This unique day of continuing education programming is open to everyone and will offer excellent networking opportunities and deep dives into neurology fundamentals. You can register for the APP Pre-conference on a stand-alone basis but will receive the best value by bundling it with the full Fall Conference.

Practice management courses combine both physician and business administrator talks to offer practical strategies for implementation Updates and courses on the mostrelevant topics in the world of neurology today, including MS, headache, neuro rheumatology, autoimmune neurology, and brain death Special workshop on Saturday (additional fee required) More

Visit AAN.com/view/19FC to learn more about both conferences, see the full programs, and register and secure your room before September 12 deadline. 

Apply for Free FAAN Status, Set Yourself Apart Within the Academy Only approximately 12 percent of AAN members have been elected by their peers for the prestigious Fellow of the American Academy of Neurology (FAAN) designation in acknowledgement of their exemplary contributions. Applying for this elevated status is free, entirely electronic, and is an excellent way to: Set yourself apart through acknowledgement of your exemplary leadership in education, practice, and research, as well as your loyalty to and active participation in the Academy and the neurology profession

Gain eligibility to serve on the AAN Board of Directors—a unique opportunity that could allow you to have a significant impact on the future direction of the AAN

The online application process is quick and easy. Visit AAN.com/view/FAAN to learn more about eligibility requirements and to apply—or encourage a deserving colleague to apply. 

2020 Annual Meeting Abstract Submission Opens this Month continued from cover

April 25 – May 1 • Toronto, Canada

Abstracts will be accepted in all facets of neurology and neuroscience and could be chosen for Neuroscience in the Clinic sessions, Friday Grand Finale lunch with a special neuroinflammation session, and scientific platform or poster sessions. For more information, contact Erin Jackson at ejackson@aan.com or (612) 928-6112. 

Conferences & Community

Brainstorm Competition Helps Propel Winner’s Breakthrough Work Forward When Darin T. Okuda, MD, FAAN, presented his inventive idea at the inaugural, game-style Brainstorm: A Competition for the Innovator in All of Us during the 2018 Annual Meeting, he had no idea just how far his unique solution to identifying and understanding brain lesions would go. Not only did Okuda win the competition, but over the past year additional scientific achievements have been made, and his breakthrough idea is picking up steam—as well as awards and media attention along the way.

“The competition was so very great, and we’ve done such amazing things since the event,” said Okuda in talking about his team’s novel approach to advancing the concept of threedimensional phenotyping to better understand surface characteristics and structure of brain anomalies from a variety of neurological disorders—particularly MS. The approach provides more comprehensive information and clarity— including shape and texture to inform the injury and age of the lesion—than currently used 2-dimensional MRI scans. The 3D images can also help patients better understand their disease and help them follow treatment more closely.

“Since winning the Brainstorm competition, my work has expanded significantly,” said Okuda, who serves as the project’s lead investigator and professor of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center. “We’re continuing to advance the 3D concept along with developing new, more intuitive platforms that will revolutionize how we review imaging data.”

“The exposure I received from the AAN was invaluable in propelling our scientific efforts,” said Okuda, whose

revolutionary work is not going unnoticed. He’s received a number of honors since winning the Brainstorm competition, including the 2018 Reality Science Deeper Mind Award, the 2018 Best Abstract Award from the International Congress on Advanced Treatments & Technologies in Multiple Sclerosis, and the 2019 Stratasys 3-Dimensional Visualization Okuda Award. He’s also received substantial media attention, including feature articles in TechCrunch, MakerBot, Multiple Sclerosis News Today, Research Outreach, and D CEO Healthcare. Furthermore, according to Okuda, “Through the AAN’s interconnected structure, our team’s work gained an immediate audience and we’ve been fortunate to be able to partner with EMD Serono and their innovative program, MS-LINK Research Network, to improve patient care.”

Okuda was invited back to the stage at the 2019 Annual Meeting in Philadelphia to present on his many achievements over the past year. “I’m so very thankful to the AAN for creating such a platform for innovation, as this truly represents an indispensable facet in our field.” 

Do You Have an Innovative Idea You Want to Share?

We want to hear it! Now is the time to start thinking about submitting your innovative solution to challenges related to patients, practice, or any other medical-related issue to the 2020 Brainstorm: A Competition for the Innovator in All of Us at the 2020 Annual Meeting in Toronto. Email Gretchen Thielen at gthielen@aan.com to learn more. 

AANnews • September 2019 21

Education & Research

October 1 Is Last Chance to Apply for 2020 Research Program Opportunities October 1 is the last chance to apply for 20 Research Program opportunities designed to promote neurology and neuroscience research training across all discovery stages. The 2020 AAN Research Program exemplifies the AAN’s commitment to making a profound difference in the lives of researchers, which ultimately makes a difference in the lives of patients with brain disease. Visit AAN.com/view/ResearchProgram for more information and to apply for one of these opportunities:

Career Development Award Funded by the American Academy of Neurology *Two Available

Clinical Research Training Scholarship Funded by the American Academy of Neurology *Three Available

Clinical Research Training Scholarship in ALS Funded by The ALS Association and American Brain Foundation, in collaboration with the American Academy of Neurology

Clinical Research Training Scholarship in Lewy Body Diseases Funded by The Mary E. Groff Charitable Trust, the Alzheimer's Association, and the American Brain Foundation, in collaboration with the American Academy of Neurology

Clinical Research Training Scholarship in Neuromuscular Disease

Clinical Research Training Scholarship in Tourette Syndrome

Richard Olney Clinician Scientist Development Award in ALS

Funded by the Tourette Association of America and American Brain Foundation, in collaboration with the American Academy of Neurology

Funded by The ALS Association and American Brain Foundation, in collaboration with the American Academy of Neurology

McKnight Clinical Translational Research Scholarship in Cognitive Aging and Age-related Memory Loss

Robert W. Katzman, MD Clinical Research Training Scholarship in Alzheimer’s or Related Disorders

Funded by the McKnight Brain Research Foundation through the American Brain Foundation and the American Academy of Neurology *Two Available

Neuroscience Research Training Scholarship Funded by the American Academy of Neurology *Two Available

Funded by the Alzheimer's Association and the American Brain Foundation, in collaboration with the American Academy of Neurology

Susan Spencer, MD Clinical Research Training Scholarship in Epilepsy Funded by the American Epilepsy Society, the Epilepsy Foundation, and American Brain Foundation, in collaboration with the American Academy of Neurology. 

Practice Research Training Scholarship Funded by the American Academy of Neurology

Funded by the Muscle Study Group and American Brain Foundation, in collaboration with the American Academy of Neurology

Clinical Research Training Scholarship in Parkinson’s Disease Funded by the Parkinson’s Foundation and American Brain Foundation, in collaboration with the American Academy of Neurology

April 25 – May 1 • Toronto, Canada

22

AANnews • September 2019

REGISTER NOW! OCTOBER 18–20

THE COSMOPOLITAN OF LAS VEGAS Featuring an October 17 Pre-conference for Advanced Practice Providers (APPs)

Join us for the hottest topics in the field of neurology, real-world issues in practice management, and innovative science—plus valuable end-of-year CME.

New for 2019: •

Bundle with the full Fall Conference registration to save!

•

AAN.com/view/Fall

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Practice management courses with practical implementation strategies from physicians and business administrators Updates on headache, neuro rheumatology, autoimmune neurology, and brain death Saturday workshop on neuromuscular ultrasound

STUDYING THE WHOLE BRAIN MAKES A WHOLE LOT OF DIFFERENCE

28

$27M

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of awardees have gone on to secure NIH funding

projects posted on the worldâ&#x20AC;&#x2122;s first neuroscience crowdfunding platform

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Learn more about the next generation of clinical neuroscientists and their research on brain disease at AmericanBrainFoundation.org.

awarded to 244 researchers

American Brain Foundation

Mentored by Raymond Adams? Honor His Legacy and Support the Next Generation of Neurologists Raymond D. Adams, MD, (1911-2008) was a renowned researcher and visionary in the fields of neuropathology, muscle pathology, and pediatric neurology. As Bullard Professor of Neuropathology at Harvard Medical School and chief of neurology at Massachusetts General Hospital he, along with Maurice Victor, MD, authored the famous Adams and Victor's Principles of Neurology. But, perhaps more than anything, Adams is best remembered as a well-known champion of young neurologists and researchers.

In 2001, a former student of Adams’, who preferred to remain anonymous, presented the idea of supporting a research fellowship to honor the neurology giant he so admired. From that conversation sprang a chain of events that culminated in the Raymond D. Adams Clinical Research Training Fellowship in 2004. Through the generosity of that same donor, another gift of $375,000 was realized in 2018 to secure the endowment to support additional scholarships in the name of the beloved teacher, mentor, and friend, legendary neurologist, and diagnostician, who has been estimated to have trained over 250 academic neurologists in his time.

The fund is now endowed and supporting up to 15 earlycareer investigators each year who are embarking on research careers and working to discover cures to various brain diseases and conditions.

If Raymond D. Adams mentored you, or if you want to support early career researchers, you’re encouraged to: Make a gift to the Raymond Adams Fund at AmericanBrainFoundation/donate. Choose “Direct My Gift” option to direct your donation to the Raymond Adams Fund from the dropdown menu.

“He was the best teacher I ever had.

He is an exemplar to me of someone who is both a superb clinician and teacher, and who could invigorate the fields of clinical neurology, neuropathology, and pediatric neurology—and I don’t know anyone who has demonstrated these capacities in so many different fields of neuroscience.”

—James Austin, MD, one of Adams’ mentees

OR Contact Lisa Dahlberg, Personal Philanthropy Advisor, to learn more about how you can help carry Dr. Adams’ legacy forward and stand on the shoulders of this true neurology giant through a generous gift in his memory. Contact ldahlberg@americanbrainfoundation.org or (612) 928-6318. 

AANnews • September 2019 25

Education & Research

2020 AAN Award Applications Now Open Have you—or a colleague—recently achieved a milestone in your career that is deserving of significant recognition? Apply or nominate for a variety of prestigious AAN awards to be presented at the 2020 AAN Annual Meeting in Toronto. AAN awards honor the best research and achievements by neurologists and neuroscientists around the globe and at all career stages with prizes and other compensation, such as complimentary travel expenses and registration for the Annual Meeting. The application deadline is October 23. Learn more and apply or nominate at AAN.com/view/20Awards. 

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April 25 – May 1 • Toronto, Canada

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Epileptologist and Movement Disorder Neurologists.

Louisville, Kentucky, United States. Norton Neurology Services, a part of Norton Neuroscience Institute, is seeking a fellowship-trained physician to provide movement disorder services. Norton Neuroscience Institute is composed of 65 neuroscience providers, including 19 neurologists, 14 neurosurgeons, two neuropsychologists and more than 30 advanced practice providers. The ideal candidate will join three fellowship-trained epileptologists and three advanced practice providers. Our program features a six-bed, state-of the-art Level IV Epilepsy Monitoring Unit located at Norton Brownsboro Hospital. Opportunity to provide inpatient and outpatient epilepsy and general neurology services. Opportunity to participate in the annual Norton Neuroscience Institute Symposium, as well as other continuing medical education events. Weekly neuroscience clinical conference with neurosurgery and neurology providers. Research opportunities and support available through the Norton Healthcare Research Office.

Norton Neurology Services, a part of Norton Neuroscience Institute, is seeking a fellowship-trained physician to provide movement disorder services. Norton Neuroscience Institute is composed of 65 neuroscience providers, including 19 neurologists, 14 neurosurgeons, two neuropsychologists and more than 30 advanced practice providers. The ideal candidate will join two fellowship-trained movement disorder neurologists. The practice enjoys referral patterns from other neurologists in the practice as well as other physicians and providers within Norton Medical Group.

Ability to practice majority movement disorder neurology.

No mandatory system stroke call. Opportunity to provide general inpatient neurology services. Opportunity to participate in the annual Norton Neuroscience Institute Symposium, as well as other continuing medical education events. Weekly neuroscience clinical conference with

neurosurgery and neurology providers. Research opportunities and support available through the Norton Healthcare Research Office. Neurological rehabilitation services. Because of an increasing elderly population in Greater Louisville, Parkinson’s disease is a significant health concern. As the region’s leader in providing care for neurological conditions, Norton Neuroscience Institute is dedicated to offering the most advanced treatments for people with Parkinson’s disease. Cressman Neurological Rehabilitation, a service of Norton Neuroscience Institute, provides rehabilitation for patients managing neurological conditions. Patients have access to some of the most advanced technology and specialized services in one location to help with gait, balance, strength, flexibility, speech, fine motor skills, swallowing, driving, cognition, vision and more. Specialized features include the ZeroG Gait and Balance System, the Biodex Gait Training System, deep brain stimulation, Parkinson Wellness Recoverycertified therapists, videostroboscopy, and one-on one personalized training and follow-up programs. About Norton Neuroscience Institute. Established in early 2009, Norton Neuroscience Institute is the region’s leading provider of neurological care. The comprehensive program offers advanced treatment for complex neurological disorders, including ALS; aneurysms; brain tumors; epilepsy; headache and concussion; movement disorders, including Parkinson’s disease; multiple sclerosis; pediatric neurosurgery; spinal injuries and disorders; stroke; and more. In 2016, Norton Neuroscience Institute was the first in the region to use ROSA, a robotic surgical assistant, to provide advanced treatment for patients with epilepsy and brain tumors. Norton Neuroscience Institute also is one of the first in the region to use systems such as NeuroPace and NeuroBlate for performing minimally invasive surgical procedures. Patients and their families

have access to patient navigators and support services through the Norton Neuroscience Institute Resource Center, the Center for Independent Living and rehabilitation services. The resource center offers health information and assistance with getting connected to clinical trials, educational programs, support services, community resources and more to help patients live better. More information is available at NortonNeuroscienceInstitute.com.

Job Requirements: Medical degree/diploma. Residency/ fellowship certification. Kentucky medical license or license eligible. To apply for this position, contact Amanda Bailey, amanda.bailey@nortonhealthcare.org, 5(02) 439-5144. https://nortonhealthcare.com.

AANnews® Classified Advertising The AAN offers a complete package of print, online, and in-person recruitment advertising opportunities. Visit careers.AAN.com for all AAN options, rates, and deadlines. d copy for the November 2019 print edition of A AANnews must be submitted by October 1, 2019. The same deadline applies to changes/cancellations.

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