2021 October AANnews

VOLUME 33 · ISSUE 10 · OCTOBER 2021

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

REGISTRATION NOW OPEN FOR VIRTUAL FALL CONFERENCE November 5 through 7 Join the AAN and your neurology colleagues this November 5 through 7 for the fully virtual AAN Fall Conference, bringing you timely updates on the hottest topics in neurology, real-world issues in practice management, the most innovative science, valuable networking, and end-of-the-year CME. Designed specifically with attendee safety and convenience in mind, this interactive three-day experience will be accessible from anywhere there’s an internet connection, and will include live Q&A with faculty, networking opportunities, and up to 42.5 CME. Check out the six neurology update programs covering a variety of subspecialties as well as seven practice management courses covering everything from coding updates and building service lines to telemedicine and recruiting.

Registration includes access to the live virtual event, Q&A with faculty, and session recordings and program materials through Sunday, November 21—or upgrade to Gold registration for extended access to content.

Register by October 28 to Save Visit AAN.com/Fall to browse the full program and save $50 or more before the October 28 advance registration deadline! 

Mark Your Calendars for the Great Neuro Reunion!

The in-person AAN Annual Meeting is coming back!

Get ready to reunite with your neurology community in Seattle next April 2 through 7, followed by Seattle: April 2 –7 an interactive virtual Virtual: April 24–26 experience April 24 through 26. Whether you join us in person, virtually, or both, the 2022 AAN Annual Meeting is a must for taking in neurology’s most comprehensive educational offerings and largest scientific program and your chance to reconnect with your colleagues from around the globe. Registration opens later this month—sign up for notifications at AAN.com/AM. 

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Explore New APP Onboarding Resources

New Aducanumab Resources Now Available The FDA approval of the drug aducanumab for treatment of Alzheimer’s disease has raised many questions in the neurology and patient communities. The AAN continues to create, compile, and share a host of quality resources to provide answers and insights to the latest developments.

The recording of the August “Practice Perspectives for Aducanumab” webinar is available for free at AAN.com/aducanumab. The panelists in both academic and private practice settings shared their experiences and plans for how to prepare their practices to offer aducanumab to patients. Panelists responded to member questions about patient selection, workflow, monitoring for side effects, and handling costs.

22 Call for Abstracts for 2022 Annual Meeting—Submit by October 11

Continued on page 7

33 Participate in Free Webinar on Tackling Structural Racism

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AANnews · October 2021

October Highlights

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

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

Phone: (800) 879-1960 (toll free) (612) 928-6000 (international) memberservices@aan.com

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Website: AAN.com For advertising rates, contact: Michael J. O’Brien II Account/Relationship Manager Wolters Kluwer

Patient Reported Outcome Performance Measures in the Axon Registry

Quality of life and depression assessments can provide a more holistic view of a patient instead of simply focusing on disease and illness. The Axon Registry ® has implemented Patient Reported Outcome (PRO) performance measures (PRO-PM) to aid physicians and treatment teams to drive quality improvement projects for these concerns.

Phone: (978) 578-4514 Email:

Got a Practice Question? The practice @aan.com Networks Have the Answers

The practice@aan.com email inbox is an efficient way to reach staff and member expertise on practice-related topics such as payers, MIPS/MACRA, coding, and practice management.

Staff experts respond within one business day and can seek the assistance and real-world expertise of the Practice Support Network.

Contact Information American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415

Email:

Michael.Obrien @wolterskluwer.com

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

Transforming Leaders Program Graduate Transforms Life, Career

Since starting the TLP, Benzi Kluger, MD, FAAN, got married, moved across the country, started a new faculty position at the University of Rochester, began actively pursuing his dream of being a writer, and even got a smartphone.

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

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

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

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

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

News Briefs Sports Concussion Conference The 2021 Sports Concussion Conference On Demand is now available for purchase in the Online Learning Center and offers access to sessions recordings, program materials, and the ability to earn up to 10.25 hours of CME through June 30, 2022.

RITE Registration opens October 8 for the 2022 RITE® (Residency In-service Training Examination), which will take place February 15–19, 2022, and will mark the return to a proctored environment where institutions set their own testing environment and associated guidelines.

Resident Research Scholarship Encourage residents to apply for the Resident Research Scholarship, intended for neurology residents interested in a career in research. The deadline is October 24.

Contact Brooke Martin at bmartin@aan.com for additional information. 

PRESIDENT'S COLUMN Your Voice Matters When faced with difficult challenges—and since the onset of COVID-19 there have been many—I often turn to you, members of the American Academy of Neurology. The interviews I conduct for stories in Neurology Today® and, more recently, this AANnews column, help me assess the scope of problems, become aware of evolving trends, and inform my actions as your president. Since March of 2020, I have spoken to hundreds of you this way to hear what you are experiencing and how you are coping. I’ve also had many more conversations with some of you during one-on-one calls and virtual committee meetings.

I have heard you say that practicing neurology in these tentative times is immeasurably taxing, as we are a profession that normally derives joy from making a discernible difference in outcomes for our patients, not all of whom are following the science. As I write this column in late August, we are facing continued uncertainty about a novel virus as well as confronting resistance to the solutions that will destroy it. Over time, I have become aware of the invisible wounds of the pandemic: burnout, exhaustion, anxiety, depression, fear, doubt, and powerlessness. The roller coaster of hopes and disappointments has been brutal and left many re-evaluating how we conduct our lives and whether our work situations should change.

This is compounded by a sense of lagging leadership, one which has created a deterioration of trust in governance: the US Food and Drug Administration, which ignored an advisory panel vote to reject approval of aducanumab; other agencies that have been accused of inconsistent decisions regarding COVID-19 and poor communication; state governments that have banned mask orders in schools; and more.

As an organization, we have found ourselves needing to make decisions in an absence of definitive guidance and reliable data.

We have had to resort to environmental scans including valuable anecdotal information from you, our members across the world.

This boots-on-the-ground reporting made us aware that waning vaccine immunity was a reality, that our vaccinated members were contracting breakthrough COVID, and that quarantine was placing a burden on some academic departments as well as on practices.

It also led to our recognition that members were becoming increasingly worried about their immunocompromised patients. It has spurred us to action, holding an emergency board meeting on August 5 and voting on several actions including one to send a letter the following day to FDA Acting Commissioner Janet Woodcock, MD, to request that she authorize boosters to restore immunity levels for all individuals and health care providers who continue to be at risk for COVID breakthrough infections.

Advocating for our members in this COVID era means redefining what it means to be indispensable to you. This August, the Quality Committee, chaired by Lyell K. Jones, Jr., MD, FAAN, asked for the AAN to sign on to a joint statement calling for all health care employers to mandate employees be vaccinated against the SARSCoV-2 virus. Also this summer, when we heard from Academy members, especially child neurologists, about their concerns for this vulnerable segment of our patients, this committee endorsed an expansion of the AAN COVID-19 position statement advocating for continued efforts to expedite regulatory approvals and deployment of COVID-19 vaccinations for children under the age of 12 once clinical trial data support their use.

The Advocacy Committee, led by Bruce H. Cohen, MD, FAAN, has supported a call to action for a federal commission to develop a

comprehensive national plan to defeat the Avitzur long COVID, or post-acute sequelae SARSCoV-2 (PASC), crisis, and submitted a detailed letter to the Centers for Medicare & Medicaid Services advocating for revisions to the 2022 Physician Fee Schedule to continue support for telehealth services for the duration of the public health emergency. This committee also monitors and coordinates state actions such as changed laws or policies during the pandemic to require more robust insurance coverage for telehealth and supports the Interstate Medical Licensure Compact, which streamlines the licensing process for physicians who want to practice in multiple states.

Advocating for our members also means caring for our pipeline, so in late July, in consultation with other groups, the AAN Education Committee, led by Joseph I. Sirven, MD, FAAN, adopted a consensus statement regarding virtual interviews to maximize safety for applicants and programs and maintain an equitable interview process for all candidates. Prioritization of safety has likewise led to the cancellation of in-person meetings through the end of 2021, and reversion of meetings like our Fall Conference to a virtual platform.

These are but a small sampling of dozens of letters sent to regulators, legislators, and other key actions taken by our organization as committees and staff continue to diligently work on their normal daily efforts to bring members up-to-date educational and scientific initiatives and conferences.

It is rewarding when our advocacy is taken to heart. The August 23 approval of the Pfizer-BioNTech COVID-19 vaccine puts us one step closer to mandates that will ensure the safety of our patients in the workforce. And although it is rare to hear back, we received a direct response from Dr. Woodcock after only a few hours thanking the AAN for our letter advocating for boosters. We were also delighted when the agency authorized an additional vaccine dose for certain immunocompromised individuals six days later, and a joint statement from the HHS announced on August 18 that the CDC was prepared to offer Pfizer and Moderna mRNA booster shots for all Americans beginning the week of September 20 and starting eight months after an individual’s second dose. It also is anticipated booster shots will likely be needed for people who received the Johnson & Johnson vaccine.

I want to thank all of you who continue to keep me and this organization informed, our hard-working staff, and our dedicated volunteers. As we move forward during this time of crisis, please know that your voice matters and is indispensable to us. 

Orly Avitzur, MD, MBA, FAAN President, AAN oavitzur@aan.com @OrlyA on Twitter

AANnews • October 2021 3

BOARD SPOTLIGHT Meet Your New Board Member: Bruce H. Cohen, MD, FAAN Bruce H. Cohen, MD, FAAN, is the director of the NeuroDevelopmental Science Center, interim vice-president and medical director of the Rebecca D. Considine Research Institute at The Children’s Hospital Medical Center of Akron, and professor of pediatrics as well as professor of integrative medical sciences at Northeast Ohio Medical University. He holds the Rebecca D. and William Considine Chair in Research at Akron Children's Hospital. Cohen attended Washington University, graduating summa cum laude with a BA in chemistry. He received his MD degree from the Albert Einstein College of Medicine of Yeshiva University in 1982.

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

I joined the AAN as a junior member in 1985, and think I attended my first Annual Meeting in the spring of 1987 where I presented my first poster. I trained in a program that had deep roots in the AAN, so my mentors made it clear to me that the AAN was my professional home! In the early 1990s, I became involved in the Child Neurology Society’s (CNS) Practice Committee and had a strong interest in ICD-9 and CPT coding as it related to neurology services.

I believe my first AAN "committee work" began in 1995 when I was asked by Dr. Marc Nuwer to represent child neurology at CPT when the single system exam was being developed. Later, I became involved in the Child Neurology Section of the AAN and later served as chair. In 2006, I was appointed as chair of the Practice Committee of the CNS, which landed me an exofficio position on the AAN’s Practice Committee. When I was invited to join the Coding Subcommittee, I fell in love with the volunteer structure of the AAN, spending a total of 13 years (six as chair). I then became a member of the Medical Economic and Management (MEM) Committee, and then the AAN’s alternate advisor to CPT. What experiences and viewpoints do you bring to this role?

Within MEM, I also became involved in payment policy issues as I continued with my work in coding. When the committee structure was reorganized two years ago, I joined the Health Policy Subcommittee and the new Coding and Payment Policy Subcommittee—two roles that I left to assume the role of chair of the Advocacy Committee and join the Board of Directors.

During this journey, I attended almost all Annual Meetings and gave courses on coding and other practice topics. I was part of the inaugural group of Platinum Donors to BrainPAC. I see my work as adding value to the AAN, which represents American neurology in all aspects: health care delivery, science, education, practice, quality, and advocacy—advocacy for the practice of neurology and for those patients with neurologic illness and their families.

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AANnews • October 2021

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

Cohen

I have found my way onto the Board as an ex-officio officer because of my new position as chair of the Advocacy Committee.

This dual responsibility is an opportunity of my professional life.

Although advocacy seems to be a bit non-academic, the role of this Advocacy Committee and the subcommittees and programs that fall under it are enormously important to our patients and our careers that in turn support our academic and practice missions.

The time I have spent with my prior committee appointments and interests within the AAN has led me to this position, and I am thrilled to be a leader in this effort. The AAN has been a labor of love. My family, fortunately, supports me because they appreciate how much I enjoy the work.

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

I do not like to take a bully pulpit approach to this position, but one important way the AAN benefits the field of neurology is through BrainPAC, the Academy’s political action committee (PAC). I have had many AAN friends who are eligible to contribute tell me that supporting a PAC is “not my thing,” but I assure them that supporting BrainPAC “really is your thing.” BrainPAC not only gives us a stronger position to advocate for issues that are important to us, like physician reimbursement, it gives us a stronger position to ensure everyone in this country can receive the quality neurologic care they deserve. We’re not the “American Academy of Neurologists,” we’re the American Academy of Neurology. A contribution to BrainPAC is not just an investment in your professional career, but an investment in the health of your patients as well.

I am thrilled to be part of the AAN’s leadership team that will guide our organization during transition—in many ways the best time to be practicing neurology, but also a time faced with many challenges. Our actions, through BrainPAC and other advocacy channels, can help guide American medicine in the egalitarian direction where quality health care is a right for all living inside the United States. 

PRACTICE Got a Practice Question? The practice @aan.com Networks Have the Answers The practice@aan.com email inbox is an efficient way to reach staff and member expertise on practice-related topics such as payers, MIPS/MACRA, coding, and practice management. Staff experts respond within one business day and can seek the assistance and real-world expertise of the Practice Support Network, a group of 30 practicing neurologists and graduates of AAN’s Practice Leadership Program, or the Business Support Network, comprised of six business administrators in various practice settings.

Below are some common questions that have come into the inbox recently.

PRACTICE MANAGEMENT

CODING

Q: What resources are available to a neurology administrator through the AAN? How can the AAN help connect me with my colleagues?

Q: When billing based on Medical Decision Making (MDM) for outpatient E/M services, how should I count multiple tests under the Category I MDM element “Amount and/ or Complexity of Data to be Reviewed and Analyzed”? If I order a complete blood count, comprehensive metabolic panel, and a lipid panel, how many unique tests would this be considered?

A: The AAN has many resources dedicated to help business administrators (BA) and their practices thrive. If you aren’t already, consider becoming an AAN member. BA membership provides access to SynapseSM, the AAN’s online discussion boards, where you can reach your peers; free education products, such as the BA Education Series; and discounts on registration to the AAN’s conferences.

Administrators can reach colleagues in a variety of ways. In addition to Synapse, email practice@aan.com to reach the Business Support Network, where administrators are ready to help answer any practice-related questions you may have.

Early in 2022, we will be forming new BA cohorts, small groups of administrators who meet regularly to share ideas and experiences. This is a great way to build your network.

Visiting AAN.com/PracticeResources is a great place to find resources to help you and your practice. The coding resources feature up-to-date information on coding changes and best practices. The operations resources, such as the Top 5 lists and benchmarking data, can help you optimize your practice. And the value-based care resources can help you navigate the Quality Payment Program and support quality improvement in your practice.

A: This would count as three unique tests toward meeting the requirement for Category I of the MDM element. Each unique test ordered or reviewed counts and is considered unique even if they are all in the same category of test. Keep in mind, if a test is ordered and results are reviewed as part of an encounter, it is counted as only one data point.

To learn more about coding based on Medical Decision Making, review neurology specific outpatient E/M coding case studies online at AAN.com/EM.

QUALITY PAYMENT PROGRAM Q: My practice is struggling to identify which quality measures and improvement activities to report for Merit-based Incentive Payment System (MIPS) reporting this year.

How can I narrow down my options?

A: Each year, the AAN develops updated resources related to the Quality Payment Program (QPP) and MIPS, including identifying measures and activities that are most relevant to neurologists that year. The AAN’s Quality Payment Program webpage offers a resource on how to “Navigate the Quality Component of MIPS,” which includes the neurology measures available in MIPS, including measures in the Axon Registry ®. For the Improvement Activities component, the AAN has developed a resource on “Improvement Activities for Neurologists to Consider” that can help practices determine what practice improvement activities they may already be participating in and can attest to for credit in MIPS. Additionally, the Centers for Medicare & Medicaid Services has a tool to search and navigate quality measures by specialty at qpp.cms.gov.

As a reminder, CMS continues to extend the Extreme and Uncontrollable Circumstances policy for the 2021 MIPS performance year. MIPS eligible clinicians and groups may apply requesting reweighting of one or more MIPS performance categories due to the COVID-19 public health emergency. You can learn more about MIPS and regulatory relief at AAN.com/QPP. 

AANnews • October 2021 5

PRACTICE Explore New APP Onboarding Resources The AAN’s advanced practice provider community continues to grow and the Academy remains committed to developing more resources for its APP members to thrive in neurology. In addition to keeping up with the clinical demands of the practice as a neurology APP, it is important for APPs to understand how billing and coding are carried out.

The process for billing and coding can be complicated, and there are multiple ways an APP can be paid. The AAN developed a resource that describes the different ways APPs are paid under “incident-to” billing and split/shared billing.

Check out the “Understanding Billing and Coding for APPs” fact sheet on the AAN’s Team-based Care resource page.

Review more resources at AAN.com/em and AAN.com/ appresources and email practice @aan.com to share feedback, future suggestions, or questions. 

Incident-To Reimbursement: 100% of Medicare Physician Fee Schedule allowable charges Practitioner(s): APP Setting: Outpatient office setting only

Split/Share Reimbursement: 100% of Medicare Physician Fee Schedule allowable charges Practitioner(s): APP and Physician Setting: Hospital setting (inpatient, outpatient department or emergency department)

Patient Reported Outcome Performance Measures in Axon Registry Identifying relevant outcomes of importance for patients with neurologic conditions that physicians and treatment teams can change and improve over time can be difficult. Patients and care partners have identified quality of life and depression as outcomes that are important and meaningful to evaluate during a neurologic visit. Quality of life and depression assessments can provide a more holistic view of a patient instead of simply focusing on disease and illness. The Axon Registry® has implemented Patient Reported Outcome (PRO) performance measures (PRO-PM) to aid physicians and treatment teams to drive quality improvement projects for these concerns.

Below are the three current PRO-PMs in the Axon Registry, which can be found at AAN.com/Axon.

Axon 41: Quality of Life Outcome for Patients with Epilepsy The purpose of this measure is to review whether the quality of life score for an epilepsy patient 18 years and older has been maintained or improved over time using PRO questionnaire QOLIE-10-P. Axon 42: Depression Remission at 12 Months The purpose of this measure is to review the percentage of adolescent patients between the ages of 12 to 17 years of age

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AANnews • October 2021

and adult patients aged 18 years and older diagnosed with major depression or dysthymia who have experienced remission over the past 12 months.

Axon 54: Quality of Life Outcome for Patients with Neurologic Conditions The purpose of this measure is to review whether quality of life score for a patient 18 years and older has been maintained or improved over time using PRO questionnaire PROMIS Global Health-10. This measure directly assesses quality

of life outcomes for patients across neurology.

These three PRO-PMs focus on tracking outcomes. There are several additional measures in the Axon Registry to focus on physician collection of PRO data. These process measures rely on additional PRO tools for patients with dementia, multiple sclerosis, Parkinson’s disease, polyneuropathy, and more.

AANnews recently highlighted ways to implement PRO data in its March, June, and September 2021 editions. The AAN has further resources on PRO collection available at AAN.com/pro. If you are interested in joining the Axon Registry, you can reach out to registry@aan.com for further details. 

New Aducanumab Resources Now Available continued from cover Neurology practices are navigating these questions amid uncertainty around insurance coverage. With the vast majority of patients expected to be in the Medicare population, CMS is in the midst of the process to consider a national coverage determination for aducanumab and other expected future monoclonal antibodies for treatment of Alzheimer’s disease. In August, the AAN submitted comments (see AAN.com/aducanumab) about meaningful health outcomes for patients, issues of equity and inclusion, and the treatment team and setting for giving the treatment. CMS is expected to provide a final coverage decision by April 2022. In the meantime, regional Medicare administrative contractors may make their own coverage decisions.

The Aducanumab Resources page at AAN.com/aducanumab is updated regularly with new articles and resources. The AAN has made available for free to all members two courses from the 2021 Annual Meeting that cover basic concepts of anti-amyloid therapies and the clinical trial data as well as a debate about whether amyloid beta is a good target for Alzheimer’s disease. 

AAN.com/aducanumab

Get recognized for your outstanding achievement in neurology.

Apply—or nominate a deserving colleague—for a prestigious AAN award

by October 28, 2021

AAN.com/Awards

FOR PATIENTS WITH RELAPSING FORMS OF MS

PLAYING WITH FEWER RELAPSES • The efficacy of VUMERITY® (diroximel fumarate) is based upon bioavailability studies in patients with relapsing forms of multiple sclerosis and healthy subjects comparing dimethyl fumarate to VUMERITY1 • Study 1: A 2-year, randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. Primary endpoint: PPR1 • Study 2: A 2-year, multicenter, randomized, double-blind, placebo-controlled study in 1417 patients with RRMS. Primary endpoint: ARR1

VUMERITY offers the efficacy demonstrated by dimethyl fumarate across 2 pivotal trials1

of treated patients were relapse-free at 2 years1

• Dimethyl fumarate demonstrated a 49% and 34% relative risk reduction in PPR vs placebo, respectively (27% vs 46%; P<0.0001), (29% vs 41%; P=0.0020)

Based on ARR, treated patients experienced

RELAPSE every 2 years1

• Dimethyl fumarate demonstrated a 53% and 44% relative reduction in ARR vs placebo, respectively (0.172 vs 0.364; P<0.0001), (0.224 vs 0.401; P<0.0001)

Visit www.vumerityhcp.com

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

Important Safety Information CONTRAINDICATIONS

VUMERITY is contraindicated in patients • With known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY. Reactions may include anaphylaxis and angioedema • Taking dimethyl fumarate

WARNINGS AND PRECAUTIONS

Anaphylaxis and Angioedema • VUMERITY can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in patients taking dimethyl fumarate (which has the same active metabolite as VUMERITY) have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue VUMERITY and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema

Progressive Multifocal Leukoencephalopathy • Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate (which has the same active metabolite as VUMERITY). PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial • PML has occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9 × 109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8×109/L persisting for more than 6 months • At the first sign or symptom suggestive of PML, withhold VUMERITY and perform an appropriate diagnostic evaluation.

Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes

Important Safety Information (cont'd) WARNINGS AND PRECAUTIONS (CONT'D)

Progressive Multifocal Leukoencephalopathy (cont'd) • Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present Herpes Zoster and Other Serious Opportunistic Infections • Serious cases of herpes zoster have occurred in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY), including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on VUMERITY for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered • Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment • Consider withholding VUMERITY treatment in patients with herpes zoster or other serious infections until the infection has resolved Lymphopenia • VUMERITY may decrease lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (which has the same active metabolite as VUMERITY), mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable.

Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with dimethyl fumarate or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 109/L or ≤0.5 x 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years) • In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced lymphocyte counts <0.5 x 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. Neither VUMERITY nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts • Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with VUMERITY, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of VUMERITY in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if VUMERITY is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution Liver Injury • Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY) in the postmarketing setting.

The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities © 2021 Biogen. All rights reserved. 07/21 VUM-US-0458 v4

resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients • Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials with dimethyl fumarate • Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during treatment as clinically indicated. Discontinue VUMERITY if clinically significant liver injury induced by VUMERITY is suspected Flushing • VUMERITY may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials of dimethyl fumarate (which has the same active metabolite as VUMERITY), 40% of dimethyl fumarate-treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization

ADVERSE REACTIONS • The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate (which has the same active metabolite as VUMERITY) were flushing, abdominal pain, diarrhea, and nausea • Gastrointestinal adverse reactions: Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with dimethyl fumarate compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with dimethyl fumarate • Hepatic transaminases: An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate was seen primarily during the first six months of treatment and most patients with elevations had levels <3 times the upper limit of normal (ULN) during controlled trials. There were no elevations in transaminases ≥ 3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with dimethyl fumarate or placebo • Eosinophilia adverse reactions: A transient increase in mean eosinophil counts was seen during the first 2 months of therapy

USE IN SPECIFIC POPULATIONS

Renal Impairment • No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite, use of VUMERITY is not recommended in patients with moderate or severe renal impairment Please see following pages for Brief Summary of full Prescribing Information.

PPR=proportion of patients relapsed; ARR=annualized relapse rate.

Reference: 1. VUMERITY Prescribing Information, Biogen, Cambridge, MA.

VUMERITY® (diroximel fumarate) delayed-release capsules, for oral use Brief Summary of full Prescribing Information 1. INDICATIONS AND USAGE VUMERITY is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsingremitting disease, and active secondary progressive disease, in adults.

2. DOSAGE AND ADMINISTRATION 2.1 Blood Tests Prior to Initiation of VUMERITY Obtain the following prior to treatment with VUMERITY: • A complete blood cell count (CBC), including lymphocyte count [see Warnings and Precautions (5.4)] • Serum aminotransferase, alkaline phosphatase, and total bilirubin levels [see Warnings and Precautions (5.5)] 2.2 Dosing Information The starting dosage for VUMERITY is 231 mg twice a day orally. After 7 days, the dosage should be increased to the maintenance dosage of 462 mg (administered as two 231 mg capsules) twice a day orally.

Temporary dosage reductions to 231 mg twice a day may be considered for individuals who do not tolerate the maintenance dosage. Within 4 weeks, the recommended dosage of 462 mg twice a day should be resumed. Discontinuation of VUMERITY should be considered for patients unable to tolerate return to the maintenance dosage.

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

2.3 Administration Instructions Swallow VUMERITY capsules whole and intact. Do not crush or chew, or sprinkle the capsule contents on food.

If taken with food, avoid a high-fat, high-calorie meal/snack; the meal/snack should contain no more than 700 calories and no more than 30 g fat [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Avoid co-administration of VUMERITY with alcohol [see Clinical Pharmacology (12.3)].

of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial.

During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years) while taking dimethyl fumarate [see Warnings and Precautions (5.4)]. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.

PML has also occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9 × 109/L).

While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8×109/L persisting for more than 6 months.

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

Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Cases of PML diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present.

Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

2.4 Blood Tests to Assess Safety After Initiation of VUMERITY Obtain a complete blood cell count (CBC), including lymphocyte count, 6 months after initiation of VUMERITY and then every 6 to 12 months 5.3 Herpes Zoster and Other Serious Opportunistic Infections thereafter, as clinically indicated [see Warnings and Precautions (5.4)].

Serious cases of herpes zoster have occurred in patients treated Obtain serum aminotransferase, alkaline phosphatase, and total with dimethyl fumarate (which has the same active metabolite as bilirubin levels during treatment with VUMERITY, as clinically indicated VUMERITY) including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster [see Warnings and Precautions (5.5)]. meningomyelitis. These events may occur at any time during treatment.

2.5 Patients With Renal Impairment Monitor patients on VUMERITY for signs and symptoms of herpes No dosing adjustment is recommended in patients with mild renal zoster. If herpes zoster occurs, appropriate treatment for herpes zoster impairment. should be administered.

VUMERITY is not recommended in patients with moderate or severe Other serious opportunistic infections have occurred with dimethyl renal impairment [see Use in Specific Populations (8.6) and Clinical fumarate, including cases of serious viral (herpes simplex virus, Pharmacology (12.3)].

West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium 3. DOSAGE FORMS AND STRENGTHS These infections have been reported in VUMERITY is available as hard, delayed-release capsules containing tuberculosis) infections.

231 mg of diroximel fumarate. The capsules have a white cap and a patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, white body, printed with “DRF 231 mg” in black ink on the body. meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and 4. CONTRAINDICATIONS ear. Patients with symptoms and signs consistent with any of these VUMERITY is contraindicated in patients infections should undergo prompt diagnostic evaluation and receive • With known hypersensitivity to diroximel fumarate, dimethyl appropriate treatment. fumarate, or to any of the excipients of VUMERITY. Reactions Consider withholding VUMERITY treatment in patients with herpes may include anaphylaxis and angioedema [see Warnings and zoster or other serious infections until the infection has resolved [see Precautions (5.1)].

Adverse Reactions (6.2)].

• Taking dimethyl fumarate [see Drug Interactions (7.1)].

5.4 Lymphopenia 5. WARNINGS AND PRECAUTIONS VUMERITY may decrease lymphocyte counts. In the MS placebo5.1 Anaphylaxis and Angioedema controlled trials with dimethyl fumarate (which has the same active VUMERITY can cause anaphylaxis and angioedema after the first metabolite as VUMERITY), mean lymphocyte counts decreased by dose or at any time during treatment. Signs and symptoms in patients approximately 30% during the first year of treatment with dimethyl taking dimethyl fumarate (which has the same active metabolite as fumarate and then remained stable. Four weeks after stopping dimethyl VUMERITY) have included difficulty breathing, urticaria, and swelling fumarate, mean lymphocyte counts increased but did not return to of the throat and tongue. Patients should be instructed to discontinue baseline. Six percent (6%) of dimethyl fumarate patients and <1% of VUMERITY and seek immediate medical care should they experience placebo patients experienced lymphocyte counts <0.5 × 109/L (lower signs and symptoms of anaphylaxis or angioedema. limit of normal 0.91 × 109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with 5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred in dimethyl fumarate or placebo, respectively. There was no increased infections observed in patients with lymphocyte patients with MS treated with dimethyl fumarate (which has the same incidence of serious 9 9 active metabolite as VUMERITY). PML is an opportunistic viral infection counts <0.8 × 10 /L or ≤0.5 × 10 /L in controlled trials, although one

patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years) [see Warnings and Precautions (5.2)].

In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced lymphocyte counts <0.5 × 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 × 109/L with continued therapy. Neither VUMERITY® (diroximel fumarate) nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts.

Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with VUMERITY, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of VUMERITY in patients with lymphocyte counts less than 0.5 × 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if VUMERITY is discontinued or interrupted because of lymphopenia.

Consider withholding treatment from patients with serious infections until resolution. Decisions about whether or not to restart VUMERITY should be individualized based on clinical circumstances.

The data described in the following sections were obtained using dimethyl fumarate delayed-release capsules, which has the same active metabolite as VUMERITY. Adverse Reactions in Placebo-Controlled Trials with Dimethyl Fumarate In the two well-controlled studies demonstrating effectiveness, 1529 patients received dimethyl fumarate with an overall exposure of 2244 person-years [see Clinical Studies (14)].

The adverse reactions presented in Table 1 below are based on safety information from 769 patients treated with dimethyl fumarate 240 mg twice a day and 771 placebo-treated patients. The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea.

Table 1: Adverse Reactions in Study 1 and 2 Reported for Dimethyl Fumarate at ≥2% Higher Incidence than Placebo

Adverse Reactions

Dimethyl Fumarate 240 mg Twice Daily (N=769) %

Placebo (N=771)%

5.5 Liver Injury Clinically significant cases of liver injury have been reported in patients 40 6 treated with dimethyl fumarate (which has the same active metabolite Flushing as VUMERITY) in the postmarketing setting. The onset has ranged Abdominal pain 18 10 from a few days to several months after initiation of treatment with 14 11 dimethyl fumarate. Signs and symptoms of liver injury, including Diarrhea elevation of serum aminotransferases to greater than 5-fold the upper Nausea 12 9 limit of normal and elevation of total bilirubin to greater than 2-fold Vomiting 9 5 the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required Pruritus 8 4 hospitalization. None of the reported cases resulted in liver failure, Rash 8 3 liver transplant, or death. However, the combination of new serum 6 4 aminotransferase elevations with increased levels of bilirubin caused Albumin urine present by drug-induced hepatocellular injury is an important predictor of Erythema 5 1 serious liver injury that may lead to acute liver failure, liver transplant, Dyspepsia 5 3 or death in some patients.

Elevations of hepatic transaminases (most no greater than 3 times Aspartate aminotransferase 4 2 the upper limit of normal) were observed during controlled trials with increased dimethyl fumarate [see Adverse Reactions (6.1)].

Lymphopenia 2 <1 Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during Gastrointestinal treatment, as clinically indicated. Discontinue VUMERITY if clinically Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, significant liver injury induced by VUMERITY is suspected. abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and 5.6 Flushing VUMERITY may cause flushing (e.g., warmth, redness, itching, and/ usually decreased over time in patients treated with dimethyl fumarate or burning sensation). In clinical trials of dimethyl fumarate (which has compared with placebo. Four percent (4%) of patients treated with the same active metabolite as VUMERITY), 40% of dimethyl fumarate- dimethyl fumarate and less than 1% of placebo patients discontinued treated patients experienced flushing. Flushing symptoms generally due to gastrointestinal events. The incidence of serious GI events was began soon after initiating dimethyl fumarate and usually improved 1% in patients treated with dimethyl fumarate. or resolved over time. In the majority of patients who experienced Hepatic Transaminases flushing, it was mild or moderate in severity. Three percent (3%) of An increased incidence of elevations of hepatic transaminases in patients discontinued dimethyl fumarate for flushing and <1% had patients treated with dimethyl fumarate was seen primarily during serious flushing symptoms that were not life-threatening but led the first six months of treatment, and most patients with elevations to hospitalization. had levels <3 times the upper limit of normal (ULN) during controlled Administration of VUMERITY with food may reduce the incidence of trials. Elevations of alanine aminotransferase and aspartate flushing [see Dosage and Administration (2.3)]. Studies with dimethyl aminotransferase to ≥3 times the ULN occurred in a small number of fumarate show that administration of non-enteric coated aspirin (up to patients treated with both dimethyl fumarate and placebo and were a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence balanced between groups. There were no elevations in transaminases or severity of flushing [see Clinical Pharmacology (12.3)]. ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases 6. ADVERSE REACTIONS The following important adverse reactions are described elsewhere were <1% and were similar in patients treated with dimethyl fumarate or placebo. in labeling: • Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)] Eosinophilia • Progressive Multifocal Leukoencephalopathy [see Warnings and A transient increase in mean eosinophil counts was seen during the Precautions Section (5.2)] first 2 months of therapy.

• Herpes Zoster and Other Serious Opportunistic Infections [see Adverse Reactions in Clinical Studies with VUMERITY Warnings and Precautions (5.3)] In clinical studies assessing safety in patients with RRMS, approximately • Lymphopenia [see Warnings and Precautions (5.4)] 700 patients were treated with VUMERITY and approximately • Liver Injury [see Warnings and Precautions (5.5)] 490 patients received more than 1 year of treatment with VUMERITY. • Flushing [see Warnings and Precautions (5.6)] The adverse reaction profile of VUMERITY was consistent 6.1 Clinical Trials Experience with the experience in the placebo-controlled clinical trials with Because clinical trials are conducted under widely varying conditions, dimethyl fumarate. adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval not reflect the rates observed in clinical practice.

use of dimethyl fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver function abnormalities (elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN) have been reported following dimethyl fumarate administration in post marketing experience [see Warnings and Precautions (5.5)].

Herpes zoster infection and other serious opportunistic infections have been reported with dimethyl fumarate administration in postmarketing experience [See Warnings and Precautions (5.3)].

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of VUMERITY® (diroximel fumarate) or dimethyl fumarate (which has the same active metabolite as VUMERITY) in pregnant women. In animal studies, administration of diroximel fumarate during pregnancy or throughout pregnancy and lactation resulted in adverse effects on embryofetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposures [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.

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

Dosage and Administration Inform patients that they will be provided a starter dose bottle: one capsule twice a day for the first 7 days and then two capsules twice a day thereafter. Advise patients to take VUMERITY as instructed.

Inform patients to swallow VUMERITY capsules whole and intact.

Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that they should avoid a high-fat, high-calorie meal/snack at the time they take VUMERITY. If taken with food, the meal/snack should contain no more than 700 calories and no more than 30 g fat. Advise patients to avoid co-administration of VUMERITY with alcohol [see Dosage and Administration (2.2)].

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

Progressive Multifocal Leukoencephalopathy Inform patients that progressive multifocal leukoencephalopathy (PML) has occured in patients who received dimethyl fumarate, and therefore may occur with VUMERITY. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Inform the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms Data associated with PML are diverse, progress over days to weeks, and Animal Data include progressive weakness on one side of the body or clumsiness Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/ of limbs, disturbance of vision, and changes in thinking, memory, day) to pregnant rats throughout organogenesis resulted in a decrease and orientation leading to confusion and personality changes [see in fetal body weight and an increase in fetal skeletal variations at the Warnings and Precautions (5.2)]. highest dose tested, which was associated with maternal toxicity.

Plasma exposures (AUC) for MMF and HES (the major circulating drug- Herpes Zoster and Other Serious Opportunistic Infections related compound in humans) at the no-effect dose (100 mg/kg/day) Inform patients that herpes zoster and other serious opportunistic for adverse effects on embryofetal development were approximately infections have occurred in patients who received dimethyl fumarate 2 times those in humans at the recommended human dose (RHD) of and therefore may occur with VUMERITY. Instruct the patient of the importance of contacting their doctor if they develop any signs or 924 mg/day.

Oral administration of diroximel fumarate (0, 50, 150, or 350 mg/kg/ symptoms associated with herpes zoster or other serious opportunistic day) to pregnant rabbits throughout organogenesis resulted in an infections [see Warnings and Precautions (5.3)]. increase in fetal skeletal malformations at the mid and high doses and Lymphocyte Counts reduced fetal body weight and increases in embryofetal death and Inform patients that VUMERITY may decrease lymphocyte counts. A fetal skeletal variations at the highest dose tested. The high dose was blood test should be obtained before they start therapy. Blood tests are associated with maternal toxicity. Plasma exposures (AUC) for MMF also recommended after 6 months of treatment, every 6 to 12 months and HES at the no-effect dose (50 mg/kg/day) for adverse effects on thereafter, and as clinically indicated [see Warnings and Precautions embryofetal development were similar to (MMF) or less than (HES) (5.4) and Adverse Reactions (6.1)]. those in humans at the RHD. Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/day) Liver Injury to rats throughout gestation and lactation resulted in reduced weight, Inform patients that VUMERITY may cause liver injury. Instruct which persisted into adulthood, and adverse effects on neurobehavioral patients treated with VUMERITY to report promptly to their healthcare function in offspring at the highest dose tested. Plasma exposures provider any symptoms that may indicate liver injury, including fatigue, (AUC) for MMF and HES at the no-effect dose for adverse effects on anorexia, right upper abdominal discomfort, dark urine, or jaundice. A postnatal development (100 mg/kg/day) were approximately 3 times blood test should be obtained before patients start therapy and during treatment, as clinically indicated [see Warnings and Precautions (5.5)].

(MMF) or similar to (HES) those in humans at the RHD. 8.2 Lactation Risk Summary There are no data on the presence of diroximel fumarate or metabolites (MMF, HES) in human milk. The effects on the breastfed infant and on milk production are unknown.

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

8.4 Pediatric Use Safety and effectiveness established.

in

pediatric

patients

have

not

Flushing and Gastrointestinal (GI) Reactions Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions. Advise patients experiencing flushing that taking VUMERITY with food (avoid high-fat, high-calorie meal or snack) or taking a nonenteric coated aspirin prior to taking VUMERITY may help [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Pregnancy been Instruct patients that if they are pregnant or plan to become pregnant while taking VUMERITY they should inform their healthcare provider [see Use in Specific Populations (8.1)].

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

8.6 Renal Impairment No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite [2-hydroxyethyl succinimide (HES)], use of VUMERITY is not recommended in patients with moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

Manufactured for: Biogen Inc. Cambridge, MA 02142 VUMERITY is a registered trademark of Biogen. © Biogen 2021

PRACTICE Epilepsy Takes Focus in New Neurology: Clinical Practice Issue The October issue of Neurology ® Clinical Practice highlights epilepsy, with research articles such as “Suicide and Seizures: a National Cohort Study in Veterans,” by Hamada Altalib, DO; “Epilepsy Treatment Complacency in Patients, Caregivers, and Healthcare Professionals,” by Patricia E. Penovich, MD, FAAN; “International Recommendations for the Management of Adults Treated with Ketogenic Diet Therapies,” by Mackenzie C. Cervenka, MD; and “The Efficacy and Use of a Pocket Card Algorithm in Status Epilepticus Treatment,” by Jessica R. Fesler, MD.

Volume 11,

Number 5,

October 202

Neurolog

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viewed clin

Epilepsy case studies include “Bruxism: A Rare, Non-lateralizing Temporal Lobe Ictal Phenomenon” by Hardik R. Doshi, MD; “Temporal Seizure Emerging from a Cluster of Eyelid Myoclonia in a Teenager with Jeavons Syndrome” by Ifrah Zawar, MD; and “A Neurostimulation Triggered Trigeminal Neuralgia-like Pain: Risk Factors and Management” by Alicia M. Goldman, MD.

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Suicide and Seizures: A National Co Veterans hort Stu RESEARCH

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Decreasing Emergency Department Children Wi Visits for th Epilepsy

Published continuously online and in print six times a year, Neurology: Clinical Practice is free to AAN members via the website (and available in print for US members only) who have a current subscription to Neurology ®. Visit Neurology.org/cp for more information. 

REVIEW

Striking MR I Changes of Fo Over Time: A Case Series cal Cortical Dysplasia and Literatur e Review CASE A Neurostim ula Neuralgia-Li tion-Triggered Trigem ina ke Pain: Ris k Factors and l Management

Moore Campaigns for Less Alzheimer’s Disease, Improved Brain Health In the decade-spanning NBC drama This Is Us, actor Mandy Moore plays Rebecca Pearson, a character who develops dementia. In real life, she has joined the nonprofit organization UsAgainstAlzheimer’s as ambassador for its Be Brain Powerful initiative, which raises awareness of brain health, especially among women. In the cover feature of the latest Brain & Life® magazine, Moore shares what she’s learned about Alzheimer’s disease and brain health from these experiences.

O C TO B E R /N OV

EMBER 2021

Exercise Pilates for Stroke and MS

Limb Spasticity Causes, Diagnosis, and Treatments Long-Haul Syndrome The Lasting Effects of COVID-19

This Is Us

or Alzheimer’s, act rk with UsAgainst Through her wo s of the disease nes are aw es Mandy Moore rais

The second feature provides an update on long-haul syndrome, a series of lingering symptoms reported by people who initially recovered from COVID-19. Doctors and researchers explain the deepening understanding of the condition and offer advice for patients on how to treat and manage it.

Limb spasticity is a common symptom of conditions such as cerebral palsy, multiple sclerosis, and brain injury. A third feature article explains how it’s diagnosed, treated, and managed.

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

AANnews • October 2021 13

ADVOCACY

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.

Latest Advocacy News In August, the AAN sent a letter to the US Food & Drug Administration urging consideration of COVID-19 vaccine boosters for US health care workers.

Subsequently, the Centers for Disease Control and Prevention announced the availability of booster shots pending a full review of the data if it has been eight months since an individual’s second dose, meaning many health care providers will become eligible Also in August, the AAN submitted comments to the Centers for Medicare & Medicaid Services (CMS) regarding its National Coverage Determination for the newly approved Alzheimer’s drug aducanumab. The comments respond to a series of clinical and technical questions posed by CMS to stakeholders.

Visit AAN.com/aducanumab to watch the AAN’s one-hour webinar on "Practice Perspectives for Aducanumab" to hear panelists discuss their preparations and challenges.

Issue in Focus The AAN advocates on issues affecting neurology at the state level, primarily supporting efforts led by state medical societies, state neurological societies, and state patient groups. Most state legislative sessions occur the first half of the year, and highlights from 2021 include:

14

AANnews • October 2021

22 states changed laws or policies during the pandemic to require more robust insurance coverage for telehealth.

Following support letters sent by the AAN, Delaware, Ohio, and Texas passed legislation to join the Interstate Medical Licensure Compact.

Texas passed prior authorization legislation to give physicians who have a 90-percent approval rating from an insurance company a “gold card,” removing prior authorization requirements for that treatment. The new law also requires peer to peer review by a Texas licensed physician of same or similar specialty.

The California Parkinson’s Disease Registry budget was increased to $8 million to expand as a Neurodegenerative Disease Registry.

The AAN also recently hosted the 2021 Neurosociety Leadership Virtual Roundtable, with leaders from 16 neurosocieties across the country. The agenda focused on membership retention strategies, return to in-person neurosociety meetings, and state advocacy. Many states are hosting in-person or virtual meetings this fall. Learn more about your state neurosociety at AAN.com/policy-andguidelines/policy/state-societies. 

EDUCATION October Continuum Offers Updates in Neurocritical Care The latest issue of Continuum: Lifelong Learning in Neurology® provides neurologists with new insights on neurocritical care.

Guest Editor Katharina M. Busl, MD, MS, FAAN, said, “Neurocritical care is a dynamic field with relevant updates even in common disease processes such as subarachnoid hemorrhage, status epilepticus, or elevated intracranial pressure. New information―prompted by the SARS-CoV-2 pandemic―includes an article on acute neurologic complications of respiratory viruses. Not only do the individual articles provide relevant updates and new findings, they also provide a framework for thinking and evaluating a critically ill patient with neurologic disease or manifestation. Especially when providing consultations in other ICUs than a neuro ICU, this issue might provide practice-based advice for many of the usually encountered scenarios.”

Busl

Content for this issue includes: Management of Cerebral Edema, Brain Compression, and Intracranial Pressure Eric M. Liotta, MD, MS

Palliative Care and Shared Decision Making in the Neurocritical Care Unit Claire J. Creutzfeldt, MD

Subarachnoid Hemorrhage Sherry Hsiang-Yi Chou, MD, MSc, FNCS, FCCM

Brain Death/Death by Neurologic Criteria Determination Ariane Lewis, MD; Matthew P. Kirschen, MD, PhD

Intracerebral Hemorrhage Christa O’Hana S. Nobleza, MD, MSCI Moderate and Severe Traumatic Brain Injury Christopher P. Robinson, DO, MS Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome as Syndromes of Cerebrovascular Dysregulation Aneesh B. Singhal, MD, FAAN, FANA, FAHA Seizures, Status Epilepticus, and Continuous EEG in the Intensive Care Unit Eric S. Rosenthal, MD Neuromuscular Disorders in the Intensive Care Unit Torrey Boland Birch, MD

The issue includes a postreading self-assessment and test with the opportunity to earn up to 20 AMA PRA Category 1 Credits™ toward Self-assessment CME. The remaining topic for 2021 is Behavioral Neurology and Psychiatry.

AAN members pay only $399 per year for a subscription to Continuum® and Continuum® Audio. Subscribe now by contacting Wolters Kluwer at (800) 361-0633 or (301) 223-2300 (international) or visit shop.lww.com/continuum. AAN Junior members who are transitioning to neurologist memberships are eligible to receive a 60-percent discount on the already low member rate for the Continuum and Continuum Audio subscription. 

Acute Neurologic Manifestations of Respiratory Viruses Michael A. Pizzi, DO, PhD Neurologic Complications in the Postoperative Neurosurgery Patient Aarti Sarwal, MD, FAAN Neurologic Outcome Prediction in the Intensive Care Unit Carolina B. Maciel, MD, MSCR

OCTOBER 2021

VOL. 27

NO. 5

Neurocritical Care EDITOR-IN-CHIEF: STEVEN L. LEWIS, MD, FA AN GUEST EDITOR: NAME TEEK AY, MD

CONTINUUMJOURNAL.COM

AANnews • October 2021 15

NIGHTTIME DOSING

DAYTIME COVERAG NIGHTTIME D

For Parkinson's disease patients with motor complications,1,2

GOCOVRI® COULD MEAN THE DIFFERENCE

BETWEEN GETTING UP

AND GETTING OUT GOCOVRI® is ready when your Parkinson’s disease (PD) patients with dyskinesia or OFF episodes need it.2 With a single nighttime dose, high levels of GOCOVRI® are reached by morning before the first levodopa dose, providing all-day coverage with levels slowly decreasing in the hours before bedtime.2 In clinical trials, GOCOVRI® reduced PD dyskinesia (primary endpoint) and OFF time and increased GOOD ON time (secondary endpoints).1 *

INDICATION GOCOVRI® (amantadine) extended release capsules is indicated: • For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications • As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes It is not known if GOCOVRI is safe and effective in children.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2.

WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported

falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases.

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose.

GE OSING

GOCOVRI® is the first and only treatment approved for dyskinesia, OFF episodes, or both in PD patients taking levodopa.1

DAYTIME COVERAGE

Not an actual patient.

27% DECREASE IN DYSKINESIA 36% DECREASE IN OFF TIME 29% INCREASE IN GOOD ON TIME

10.1-point reduction in UDysRS score (-17.7 GOCOVRI® vs -7.6 placebo) 3†

1-hour decrease (-0.6 GOCOVRI® vs 0.4 placebo) 3,4†

GOOD ON time, ON time without troublesome dyskinesia; UDysRS, Unified Dyskinesia Rating Scale.

2.4-hour increase (3.8 GOCOVRI® vs 1.4 placebo) 3,4†

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges.

Consider dose reduction or stopping medications.

ADVERSE REACTIONS The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

Visit GocovriHCP.com to learn more.

*As seen in pooled results of 2 independently positive, pivotal, Phase 3, randomized, placebo-controlled trials (Study 1 and Study 2) in PD patients on levodopa. Study 1, a 24-week study, was conducted in 121 PD patients with dyskinesia (GOCOVRI® [n = 63], placebo [n = 58]). Study 2, a 12-week study, was conducted in 75 PD patients with dyskinesia (GOCOVRI® [n = 37], placebo [n = 38]).1,3 † In Study 1, GOCOVRI® reduced the UDysRS total score by 15.9 points (vs 8.0 with placebo) (P = 0.0009), decreased OFF time by 0.6 hours (vs an increase of 0.3 hours with placebo) (P = 0.0171), and increased GOOD ON time by 3.6 hours (vs 0.8 hours with placebo) (P < 0.0001) from baseline. In Study 2, GOCOVRI® reduced the UDysRS total score by 20.7 points (vs 6.3 with placebo) (P < 0.0001), decreased OFF time by 0.5 hours (vs an increase of 0.6 hours with placebo) (P = 0.0199), and increased GOOD ON time by 4.0 hours (vs 2.1 hours with placebo) (P = 0.0168) from baseline.1

Please see Brief Summary of full Prescribing Information on the adjacent page.

Adamas and Gocovri are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies. © 2021 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved. GOC-0759 v2 04/21

GOCOVRI® (amantadine) extended release capsules Brief Summary of full Prescribing Information. See full Prescribing Information.

Rx Only.

INDICATIONS AND USAGE: GOCOVRI® (amantadine) extended release capsules is indicated: • For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications • As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes CONTRAINDICATIONS: Contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2 WARNINGS AND PRECAUTIONS: Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported in 4% vs 1% of patients treated with GOCOVRI or placebo, respectively. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (eg, driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence.

Suicidality and Depression: In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% vs 0%; depression or depressed mood 6% vs 1%; confusional state 3% vs 2%; apathy 2% vs 0%, of patients treated with GOCOVRI or placebo, respectively. Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis.

In controlled trials, the incidence of patients who experienced visual hallucination, auditory hallucination, delusions, illusions, or paranoia was 25% vs 3%; hallucinations caused discontinuation of treatment in 8% vs 0%; of patients treated with GOCOVRI or placebo, respectively. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases.

Dizziness and Orthostatic Hypotension: In controlled clinical trials, 29% vs 2% experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension; and 3% vs 0% discontinued study treatment because of dizziness, postural dizziness, or syncope; of patients receiving GOCOVRI or placebo, respectively. Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol with GOCOVRI is not recommended.

Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech.

If possible, avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of such urges, and to consider dose reduction or stopping GOCOVRI treatment.

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. GOCOVRI was evaluated in 2 double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients). The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for 1 week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Study 1 was stopped prematurely unrelated to safety, with 39/100 patients (safety population) treated with GOCOVRI for 24 weeks.

The most common adverse reactions reported in >10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.

The overall rate of discontinuation because of adverse reactions was 20% vs 8% for patients treated with GOCOVRI or placebo, respectively. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucination (8% GOCOVRI vs 0% placebo), dry mouth (3% GOCOVRI vs 0% placebo), peripheral edema (3% GOCOVRI vs 0% placebo), blurred vision (3% GOCOVRI vs 0% placebo), postural dizziness and syncope (2% GOCOVRI vs 0% placebo), abnormal dreams (2% GOCOVRI vs 1% placebo), dysphagia (2% GOCOVRI vs 0% placebo), and gait disturbance (2% GOCOVRI vs 0% placebo).

Pooled Analysis of Adverse Reactions Reported for ≥3% of Patients Treated With GOCOVRI 274 mg (n=100) or placebo (n=98), respectively: Psychiatric disorders: visual and/or auditory hallucination (21%, 3%); anxiety and/ or generalized anxiety (7%, 3%); insomnia (7%, 2%); depression/depressed mood (6%, 1%); abnormal dreams (4%, 2%); confusional state (3%, 2%) Nervous system disorders: dizziness (16%, 1%); headache (6%, 4%); dystonia (3%, 1%) Gastrointestinal disorders: dry mouth (16%, 1%); constipation (13%, 3%); nausea (8%, 3%); vomiting (3%, 0%) General disorders and administration-site conditions: peripheral edema (16%, 1%); gait disturbance (3%, 0%) Injury, poisoning, and procedural complications: fall (13%, 7%); contusion (6%, 1%) Infections and infestations: urinary tract infection (10%, 5%) Skin and subcutaneous tissue disorders: livedo reticularis (6%, 0%); pigmentation disorder (3%, 0%) Metabolism and nutrition disorders: decreased appetite (6%, 1%) Vascular disorders: orthostatic hypotension, including postural dizziness, syncope, presyncope, and hypotension (13%, 1%) Eye disorders: blurred vision (4%, 1%); cataract (3%, 1%);

dry eye (3%, 0%) Musculoskeletal and connective tissue disorders: joint swelling (3%, 0%), muscle spasm (3%, 0%) Reproductive system and breast disorders: benign prostatic hyperplasia—all male (6%, 2%) Respiratory, thoracic, and mediastinal disorders: cough (3%, 0%). Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia.

Difference in the Frequency of Adverse Reactions by Gender in Patients Treated With GOCOVRI Adverse reactions reported more frequently in women (n=46) vs men (n=54) were: dry mouth (22% vs 11%), nausea (13% vs 4%), livedo reticularis (13% vs 0%), abnormal dreams (9% vs 0%), and cataracts (7% vs 0%), respectively. Men vs women reported the following adverse reactions more frequently: dizziness (20% vs 11%), peripheral edema (19% vs 11%), anxiety (11% vs 2%), orthostatic hypotension (7% vs 2%), and gait disturbance (6% vs 0%), respectively.

Difference in the Frequency of Adverse Reactions by Age in Patients Treated With GOCOVRI Hallucinations (visual or auditory) were reported in 31% of patients age 65 years and over (n=52) vs 10 % in patients below the age of 65 years (n=48). Falls were reported in 17% of patients age 65 and over vs 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over compared with 2% of patients below age 65.

DRUG INTERACTIONS: Other Anticholinergic Drugs: Products with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. The dose of anticholinergic drugs or of GOCOVRI should be reduced if atropine-like effects appear when these drugs are used concurrently.

Drugs Affecting Urinary pH: The pH of the urine has been reported to influence the excretion rate of amantadine. Urine pH is altered by diet, drugs (eg, carbonic anhydrase inhibitors, sodium bicarbonate), and clinical state of the patient (eg, renal tubular acidosis or severe infections of the urinary tract). Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. Alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions.

Monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively.

Live Attenuated Influenza Vaccines: Due to its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live vaccines are not recommended during treatment with GOCOVRI. Inactivated influenza vaccines may be used, as appropriate.

Alcohol: Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension, and may result in dose-dumping.

USE IN SPECIFIC POPULATIONS: Pregnancy: There are no adequate data on the developmental risk associated with use of amantadine in pregnant women. Based on animal data, it may cause fetal harm.

Lactation: Amantadine is excreted into human milk, but amounts have not been quantified. There is no information on the risk to a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GOCOVRI and any potential adverse effects on the breastfed infant from GOCOVRI or from the underlying maternal condition.

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

Geriatric Use: In Phase 3 clinical trials, the mean age of patients at study entry was 65 years. Of the total number of patients in clinical studies of GOCOVRI, 46% were less than 65 years of age, 39% were 65-74 years of age, and 15% were 75 years of age or older. Hallucinations and falls occurred more frequently in patients 65 years of age or older, compared with those less than 65 years of age. No dose adjustment is recommended on the basis of age. GOCOVRI is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment: GOCOVRI is contraindicated for use in patients with end-stage renal disease (creatinine clearance values lower than 15 mL/min/1.73 m2). A 50% dose reduction of GOCOVRI to a starting daily dose of 68.5 mg daily for a week, followed by a daily maintenance dose of 137 mg is recommended in patients with moderate renal impairment (creatinine clearance between 30 and 59 mL/min/1.73 m2). For patients with severe renal impairment (creatinine clearance between 15 and 29 mL/min/1.73 m2), a daily dose of 68.5 mg is recommended.

Overdosage: Deaths have been reported from overdose with amantadine immediate-release. The lowest reported acute lethal dose was 1 g of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction, including increased BUN and decreased creatinine clearance, can occur. Central nervous system effects that have been reported with overdose include agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor, disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has occurred with amantadine overdose. For acute overdosing, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary. The excretion rate of amantadine increases with acidification of urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes. Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias. Monitor blood electrolytes, urine pH, and urinary output.

Although amantadine is not efficiently removed by hemodialysis, this procedure may be useful in the treatment of amantadine toxicity in patients with renal failure.

References: 1. GOCOVRI® (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2021. 2. Hauser RA, Pahwa R, Wargin WA, et al.

Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77-88. 3. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS- 5102 (amantadine) extended-release capsules for dyskinesia in Parkinson's disease. CNS Drugs. 2018;32(4): 387-398. 4. Data on file. Adamas Pharma LLC, Emeryville, CA.

Adamas and Gocovri are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies. © 2021 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved.

GOC-0759 v2 04/21

EDUCATION Application for Accreditation of Subspecialty Fellowship Programs Due by December 1

November 5 Is Deadline to Complete 2021 Continuous Certification

Applications for subspecialty fellowship programs seeking United Council for Neurologic Subspecialties (UCNS) accreditation are due by December 1. Accreditation is a measure of training program excellence and UCNS-accredited programs demonstrate that they meet the standards of graduate medical education excellence set by both the UCNS and the subspecialty experts of each of the UCNS-recognized subspecialties. The peer-reviewed accreditation process is overseen by the Accreditation Council, a standing committee reporting to the UCNS Board of Directors. Visit UCNS.org/ Accreditation to learn more and to apply. For questions about submitting a new application or accessing your existing account, contact Amanda Carpenter at acarpenter@ucns.org. 

UCNS diplomates should complete their continuous certification (C-cert) activities by no later than November 5.

Diplomates can earn up to 11 ABPN SA credits in addition to up to 11 AMA PRA Category 1TM credits for meeting the 2021 UCNS C-cert requirements. The total credits earned are based on the actual time spent completing the 2021 C-cert activities, up to a maximum of 11 credit hours contingent on passing the C-cert quiz. Confirmation of the credits earned is emailed to diplomates within 10 business days of passing the 2021 C-cert subspecialty quiz(zes).

The American Board of Psychiatry and Neurology (ABPN) approved the 2021 C-cert program as a part of a comprehensive self-assessment (SA) program, which is mandated by the American Board of Medical Specialties as a necessary component of maintenance of certification.

C-cert provides diplomates with a relevant, effective, timely, convenient, and affordable way to meet the needs of lifelong learning and self-assessment and maintain certification.

Diplomates eligible for ABPN SA credits should attest to the credits in their ABPN Physician Folios account at ABPN.com/folios. For questions regarding ABPN certification requirements or ABPN Physician Folios accounts, contact questions@abpn.com.

Visit UCNS.org/C-cert for more information. 

AANnews • October 2021 19

EDUCATION Transforming Leaders Program Graduate Transforms Life, Career “I didn’t realize how transformative the Transforming Leaders Program (TLP) would be when I was accepted in 2018,” said Benzi Kluger, MD, FAAN. Since starting the TLP, Kluger got married, moved across the country, started a new faculty position at the University of Rochester, began actively pursuing his dream of being a writer, and even got a smartphone. “I was still using a flip phone until well into 2020, much to the amusement of my TLP classmates and chagrin of my wife,” he joked.

“Seriously though, while I can neither blame nor credit TLP for changes in my personal life, I can credit TLP for helping me succeed in several new leadership positions,” he said, referring to an impressive lineup of accomplishments in just the last few years. Since graduating, Kluger has found himself ambitiously embarking on the new roles of founding director of the University of Rochester Neuropalliative Care Service, director of a large Patient Centered Outcomes Research Institute (PCORI)-funded implementation project to make palliative care a new standard across the Parkinson Foundation’s Center of Excellence network, and founding president for the International Neuropalliative Care Society (INPCS).

“While the TLP program, coaches, and mentors helped me achieve (and expand) my goals in countless ways, I think the most valuable and enduring aspect of the program was its transformation of my approach to leadership,” explained Kluger, who initially started the INPCS project as part of his final project for the TLP program. Since then, under his newly acquired approach to leadership, INPCS has taken off like a rocket with 2021 representing a banner year with the launching of its website, membership growth, and its first virtual annual meeting. Kluger is quick to credit four key takeaways from the program as serving as inspiration for the drive and successes he’s achieved with the INPCS: Connect with Leadership Coaches “One of the biggest lessons for me from TLP was the value of coaching to prepare for leadership tasks. With INPCS this ranged from big questions, such as what precedents to set in the role of president, to small and practical matters, such as creating an agenda for our first board meeting. For some tasks I turned to professional executive coaches, but

I also turned to other leaders I admire Kluger with direct practical experience such as Dr. Andy Josephson, my TLP mentor and founding president of the Neurohospitalist Society.”

Don’t Confuse Tactics with Strategy “Getting a new society off the ground demanded that we carefully define our goals for the near and long-term (strategy) and execute the most efficient actions (tactics) to get us there. One of our current strategies is to prioritize membership growth as a means of building our foundation.

This strategy makes other tactical decisions easier; for example, to make our first annual meeting free. We’ve also made some good tactical decisions, like hiring a society management firm once we built a sufficient organizational base. This, in turn, freed our leadership from many logistical tasks, accelerating progress towards larger strategic goals.”

Develop an Appreciation for Various Leadership Styles “Early in the TLP program, our class took a leadership profile assessment. The results had the dual benefit of allowing us to see our natural strengths and blind spots, as well as to appreciate the diversity of strengths others bring into leadership roles. As an individual, this appreciation creates choices I wouldn’t otherwise see.

AAN LEADERSHIP DEVELOPMENT

Applications Open for Two Leadership Programs!

Visit AAN.com/LEAD to apply by October 13 for one of these career-enhancing opportunities: Transforming Leaders Program Created for innovative leaders with aspirations to transform their practice community and field of neurology. This multimonth program is designed to equip mid-career leaders with the advanced knowledge and skills to have greater impact and influence.

Women Leading in Neurology This empowering and inspirational leadership program is designed to help mid-career participants tackle gender disparities head-on, create a peer network with other female AAN members, and advance to the top levels of leadership in their fields and within the Academy. 

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AANnews • October 2021

For example, in creating our annual meeting agenda I could have followed my natural red energy to get things done quickly but instead wisely tapped into some green energy to get input from the entire Meeting Committee to create a thoughtful agenda that appeals to diverse attendees. In creating and working with teams, I now see diverse leadership styles as a strength and can attest to the advantages of different leadership styles for specific tasks necessary to run a society.”

Create Opportunities for Others to Grow as Leaders “A meta-lesson of the AAN TLP program is the value of investing in leadership training for current and future leaders. We see leadership training as a multiplier of value not only to INPCS but to the wider field of neuropalliative care (and to neurology, palliative medicine, medicine in general, and society). Nancy Hardaway, an executive coach and member of our board, has provided ongoing coaching to all of our officers and committee chairs from the inception of the society and will direct a workshop on leadership for committee chairs in concert with our annual meeting. We aim to make the idea of leadership as a gift that keeps on giving part of the fabric of our society.”

Added Kluger, “Coming into the program, I believed that TLP would contribute to my overall success by helping me finetune some of my managerial abilities. Coming out of the program, I saw that my actions as a leader would determine my legacy in neurology as much as my actions as a doctor, educator, or researcher (if not more so). Like these other dimensions of my career, I now saw leadership as a lifelong journey to be approached with humility, curiosity, and enthusiasm.”  Thank you to the organizations supporting this program in part:

Alnylam Pharmaceuticals, Inc. Bristol Myers Squibb Novartis Pharmaceuticals, Inc. Supernus Pharmaceuticals, Inc.

ESC: 21FC Registration#3 Ad—Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

Virtual 2021 November 5–7, 2021

Register Today!

Valuable CME. Expert Faculty. Improved Patient Care.

AAN.com/Fall

RESEARCH Call for Abstracts for 2022 Annual Meeting—Submit by October 11 Visit AAN.com/22Abstracts before October 11 at 11:59 p.m. CT to submit your abstracts for the chance to present your breakthrough research to your neurology peers from around the globe at the 2022 AAN Annual Meeting in Seattle April 2–7!

Abstracts will be accepted in all subspecialties and career levels, which makes the diversity and quality of discoveries unparalleled to other meetings. Your research might have the opportunity to be exposed to a wide audience, with past abstracts having been covered by major media outlets including the New York Times, USA Today, CNN, and more.

Previously presented abstracts will be accepted, and the submission fee is $100 for AAN members and $200 for nonmembers. Submission is free for residents and medical students.

For more information, contact science@aan.com. 

As an abstract author, the most important aspect of being involved in research is the ability to present your work to your peers, to receive feedback, and to be able to improve your science in response accordingly. The questions and comments from our peers make us dig deeper into the questions we investigate, rethink methodological approaches, and seek new meaning to our findings. Nothing can substitute for this type of scientific exchange.

Rost

— Natalia S. Rost, MD, MPH, FAHA, FAAN Chair, AAN Science Committee

Seattle: April 2 –7 Virtual: April 24–26

October 28 Application Deadline Approaching for 2022 AAN Awards Apply by October 28 for your chance to be recognized for your outstanding achievement in neurology! There’s a prestigious AAN award to honor a wide range of scientific research, advocacy, quality, and practice contributions, and recipients will be celebrated during the 2022 AAN Annual Meeting in Seattle April 2–7 and virtually April 24–26.

Visit AAN.com/Awards to learn more and to apply or nominate a colleague. 

PODCAST

NEW! $1,000 General Neurology Award This new award honors a general neurologist who has demonstrated exemplary service, performance, and/or innovation in the field.

Visit AAN.com/Awards to learn more and apply or nominate a deserving colleague by October 28. 

Neurology ® Podcast:

20 Minutes Pack a Punch!

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

22

AANnews • October 2021

MEMBERSHIP Revised AAN Code of Professional Conduct Published The AAN Board of Directors recently approved revisions to the AAN’s Code of Professional Conduct, which was published in Neurology® at Neurology.org on September 7, 2021. The AAN originally developed the code in 1993 to formalize the standards of professional behavior for Academy members to help them in their pursuit of providing the highest quality patient-centered neurologic care. Other than two sections being added in 2008 and 2009, there had not been other substantive revisions to the code since its adoption. As a service to AAN members, the Ethics, Law, and Humanities Committee (ELHC) and the AAN Board of Directors felt it was important to review the code and add or expand on certain topics made relevant by a changing world, but also being mindful of keeping within the succinct boundaries of the framework of the document.

While the ELHC and the AAN Board found great value in the original document and retained significant portions of it, the revised code contains changes (minor rewording to substantive edits) to nearly every section. Some of the revisions include: Applying the code to all categories of AAN membership to the extent applicable (previously the code applied only to neurologist members) Describing circumstances when the fiduciary duty to an individual patient may be modified by other contemporary considerations of limited resources related to a) epidemic or natural disaster (Section 1.1) or b) the time to advocate for every patient after third-party denials (Section 1.1) Addressing the management of expensive treatments: “When prescribing expensive treatments, AAN members may experience perceived conflicts between their duty to individual patients and their duty to be responsible stewards of limited health care resources. In general, the best interests of an individual patient should supersede distributive justice considerations, which should ideally be addressed at the institutional or system levels.” (Section 5.1) New sections added to address the following topics: patient safety (Section 2.6), advance directives (Section 2.7), alternative therapies (Section 2.8), patients requesting investigational treatments (Section 3.4), and respect for religious and cultural differences (Section 4.4) Several additions to further incorporate the values of inclusion, diversity, equity, anti-racism, and social justice (“IDEAS”) in applicable professional and ethical contexts, for example: “To help promote equity in neurologic care, the AAN member should consider how their own knowledge, attitudes, behavioral patterns, biases, or beliefs may contribute (by commission or omission) to inequities and disparities in their care of patients and should take remedial action to eliminate those inequities or disparities.” (Section 1.1)

“The AAN member should support and advocate for equity in both compensation and opportunities for professional advancement.” (Section 2.5) “The AAN member must make conscious efforts to foster a diverse, equitable, inclusive, and anti-racist workplace. An anti-racist workplace is generally described as a workplace that opposes racism, promotes racial tolerance, and strives towards racial equity, inclusion, awareness, and sensitivity.”

(Section 4.2) “The AAN member has an important role in advancing health and human rights for all persons and should take steps to address racism and inequity in health care. These steps may include engaging in anti-racism and bias training, advocating for changes in academic, governmental, and institutional policies that contribute to systematic racism, and participating in research studies addressing health care disparities in neurologic care.” (Section 7.2) The preface now explains the code’s use of “must” (ethically obligatory) and “should” (ethically permissible, preferable, and strongly recommended). Also, where appropriate, the revised code references various AAN position statements that provide more detailed guidance on certain topics.

The overarching goal of the code is to establish the professional standards that AAN members must or should observe in their clinical, academic, scientific, and personal activities.

To read the complete member Code of Conduct, visit AAN.com/CodeOfConduct. 

AANnews • October 2021 23

MEMBERSHIP Stay or Go: What to Consider When Changing Jobs in Times of Uncertainty If you are pondering a new chapter in your career, launch your job search during Neurology Career Week October 18–22, featuring webinars, prize giveaways, a daily Virtual Career Fair, and more. Visit careers.AAN.com to create or update a job seeker profile to claim a fun t-shirt (supplies limited). This article from the AAN’s Career Compass will help you focus on some key aspects when exploring employment opportunities.

Changing jobs can be a tough decision for any physician. Weighing the unknowns of a new role against the certainty of the current position is hard enough. Add in loyalty to the clinic or medical system and guilt over leaving patients or students, and the decision becomes even tougher. And it doesn’t help when our old friend, inertia, raises its head.

Indeed, decision theory shows that even when the current situation is uncomfortable—or downright miserable—the pull of inertia can be overwhelming.

With all of these elements in play, you might expect events like a pandemic to seal the decision to not change jobs. But in truth, the event itself could compel you to explore new work, especially if your current employer has made significant changes to your role.

So, stay or go? Whichever way your decision leans, you’ll want to consider how an uncertain event has impacted—and will continue to impact—you and your family, as well as the organization you’re with and the organizations you consider joining. Here are some things to think about when weighing the decision to change jobs.

Why leave your current role?

If you operate a private practice or work in a clinic that has been hit hard by reduced income streams during an uncertain event, the decision to leave may not be entirely in your hands. You may be laid off or furloughed, for example, or you may find that you need to close your practice. In these cases, the question won’t be “if” but “when” you will leave your current role.

In other circumstances, the decision to leave may not be clear cut. For example, you might find that your current employer has needed to shift responsibilities on your team in a way that isn’t

sustainable for you long term. You might be taking more call, for example. Or you might be assigned to duties that don’t use your neurology training, in order to fill staffing gaps elsewhere in the organization.

Of course, you might have very personal reasons influencing your decision to leave, such as family responsibilities that can’t be balanced with your current duties. Whatever your reasons for considering a change, it’s important to take the time to explore the situation. If your position is otherwise fulfilling, you would not want to give it up without verifying that the situation can’t be improved, or that you couldn’t ride it out until effects reverse course.

You’ve decided to switch jobs—now what?

If you’ve changed jobs before, this won’t be new territory for you. Given how much you, your family, and your work may have changed since events like the pandemic, you can assume your goals may have also shifted. Before jumping into the job market, it’s smart to think about what you really want in this next position.

Here are some questions to consider: Do you want essentially the same work, but in a more secure environment?

Do you want something quite different, perhaps due to changes in your personal vision and mission due to an unforeseen event?

Are you seeking a new location, perhaps to be closer to extended family?

Along with clarifying your job goal, you will also need to set a timeline for the search process: When do you want to start your new job? Counting backwards three to five months from that date provides a reasonable starting point for your outreach. If you have strong leads or offers already, the timeline could be much shorter.

As you get ready to launch your search, don’t forget to update your CV, as well as your job seeker profile in the AAN Neurology Career Center. Using resources like this will make the process more seamless and efficient.

24

AANnews • October 2021

What should you prepare for in a new position?

Unless they’re already unemployed, most job seekers prefer securing their new job before giving notice to their current employer. There’s a risk of leaving the frying pan for the fire, as they say. You don’t want to join a new organization only to learn that they are facing the same issues as the one you’re leaving.

Questions to ask potential employers will vary, depending on your specific concerns, but they might include: How has the department/clinic fared during the unpredictable environment? Are patient numbers in my area of neurology holding steady?

Have you made cuts to physician salaries or benefits?

Have you furloughed any members of the team?

Are vacation requests still being honored/funded?

What requests have you made of the neurologists this year, in terms of changed duties?

If revenues are down, what are your projections or plans for recovery?

What would be the trajectory of my career should I join the department?

MEM: 20 FAAN Recruitment Ad—Half Horizontal> AN of the chief or Whether you ask these Page questions directly Placed in AANnews department chair during an interview or conduct research 8.25 x 5.25 +0.125 bleed, 4C

have a reliable source for the information. Without someone close to the department who can tell you what’s happening there, it’s helpful to identify insiders to help develop your “read” of the situation with prospective employers.

Moving forward Remember inertia? The more confusing or pressed our lives are, the more likely we are to choose not to make a change, even when one is clearly needed. If your plan calls for a job change and you’ve identified your timeline, then it’s time to chart your steps and move forward on your plan. Otherwise, you risk losing the momentum you’ve already gained by getting this far in the process.

On the other hand, if you haven’t clearly decided, then that’s the issue you’ll want to tackle. To do that, you can either seek the information you need to make the decision or give yourself permission to table the question until a specific date in the future. This will let you break the “I really should…” loop that might otherwise be playing in your head.

Whether you stay in your job as uncertainty plays out or leave for a position that better suits your situation, making the decision itself is bound to be good medicine. With so many other ambiguities taking up bandwidth right now, it’s good to feel clarity about your career. 

before committing to a meeting may depend on whether you

SHINE A LIGHT ON YOUR ACHIEVEMENTS Apply for a prestigious Fellow of the American Academy of Neurology (FAAN) designation.

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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 relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk.

IMPORTANT SAFETY INFORMATION WARNING: Progressive Multifocal Leukoencephalopathy (PML) TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI. Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH® Prescribing Program.  Infection by the JC Virus (JCV) is required for the development of PML  There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs  Postmarketing data suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value)  MRI findings may be apparent before clinical signs or symptoms suggestive of PML. Monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present.

Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis  PML has been reported after discontinuation of TYSABRI in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least 6 months after discontinuation of TYSABRI Important Safety Information continues on the following pages. Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

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

MORE THAN

APPROXIMATELY

200,000

15 YEARS OF EXPERIENCE

NEW PATIENTS

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

in clinical trials and real-world use. Biogen is committed to patient safety through the TOUCH® Prescribing Program

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

PATIENTS TREATED

1 IN 3

DMT=disease-modifying therapy; a202,300 patients as of August 20193; b36.9% of patients as of April 2020. 4

VISIT TimeForTYSABRI.com IMPORTANT SAFETY INFORMATION (cont’d) WARNING: Progressive Multifocal Leukoencephalopathy (PML) (cont’d)  Adverse events that may occur during plasma exchange (PLEX) include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively 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. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML  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 PLEX 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 PLEX. 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  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 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) 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 Thrombocytopenia  Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of TYSABRI in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYSABRI should be discontinued Adverse Reactions  The most common adverse reactions reported at an incidence of ≥10% with TYSABRI and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%)  The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% placebo), including urinary tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%)  Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

STUDY DESCRIPTION: The AFFIRM (NAtalizumab Safety and EFFIcacy in Relapsing-Remitting MS) study was a pivotal 2-year, double-blind, randomized, controlled trial with 942 relapsing MS patients who received either TYSABRI therapy (300 mg by intravenous infusion [n=627]) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions).1,2 References: 1. TYSABRI Prescribing Information, Cambridge, MA: Biogen. 2. Polman CH, O’Connor PW, Havrdova E, et al; for the AFFIRM investigators.

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

4. Data on file as of June 2020, Biogen. © 2020 Biogen. All rights reserved. 07/20 TYS-US-2311 v3

TYSABRI (natalizumab) injection, for intravenous use Brief Summary of Full Prescribing Information WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability.

Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI [see Warnings and Precautions (5.1)].

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

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

1.

INDICATIONS AND USAGE 1.1. Multiple Sclerosis (MS) TYSABRI is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML [see Warnings and Precautions (5.1)]. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk.

2.

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

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

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

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

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

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

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

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

4.

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

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

5.

WARNINGS AND PRECAUTIONS 5.1. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received TYSABRI. Three factors that are known to increase the risk of PML in TYSABRI-treated patients have been identified: • The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. • Longer treatment duration, especially beyond 2 years.

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

These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI.

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

1/10,000

1-24 months 25-48 months 49-72 months 73-96 months

Anti-JCV Antibody Positive No Prior Prior Immunosuppressant Immunosuppressant Use Use <1/1,000 1/1,000 2/1,000 6/1,000 4/1,000 7/1,000 2/1,000 6/1,000

Notes: The risk estimates are based on postmarketing data in the United States from approximately 100,000 TYSABRI exposed patients.

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 (PLEX), 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 PLEX 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 PLEX include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively 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. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML. 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 PLEX 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 PLEX. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

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

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

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

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

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

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

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

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

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

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

Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.

Acute Retinal Necrosis Acute retinal necrosis (ARN) is a fulminant viral infection of the retina caused by the family of herpes viruses (e.g., varicella zoster, herpes simplex virus). A higher risk of ARN has been observed in patients being administered TYSABRI. Patients presenting with eye symptoms, including decreased visual acuity, redness, or eye pain, should be referred for retinal screening for ARN. Some ARN cases occurred in patients with central nervous system (CNS) herpes infections (e.g., herpes meningitis or encephalitis). Serious cases of ARN led to blindness of one or both eyes in some patients. Following clinical diagnosis of ARN, consider discontinuation of TYSABRI. The treatment reported in ARN cases included anti-viral therapy and, in some cases, surgery.

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

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

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

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

Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that patients with persistent antibodies to TYSABRI experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy

following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to TYSABRI naïve patients [see Adverse Reactions (6.2)].

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

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

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

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

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

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

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

5.8. Thrombocytopenia Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of TYSABRI in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYSABRI should be discontinued.

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

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

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

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

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

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

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

Table 2:

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

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

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2

5 <1

9 4

7 3

3 2 1

2 <1 <1

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

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

Table 3:

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

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

TYSABRI n=983 %

Placebo n=431 %

32 10 8 5 2 1

23 8 6 4 <1 <1

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

6 1

4 0

2

<1

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

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

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

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

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

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

In Studies MS1 and MS2 [see Clinical Studies (14.1)], the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients.

The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections. In Study MS1, the incidence of serious infection was approximately 3% in TYSABRItreated patients and placebo-treated patients. Most patients did not interrupt treatment with TYSABRI during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course.

In Studies CD1 and CD2 [see Clinical Studies (14.2)], the rate of any type of infection was 1.7 per patient-year in TYSABRI-treated patients and 1.4 per patient-year in placebo-treated patients. In Study CD3, the incidence of any type of infection was 1.7 per patient-year in TYSABRI-treated patients and was similar in placebo-treated patients. The most common infections were nasopharyngitis, upper respiratory tract infection, and influenza. The majority of patients did not interrupt TYSABRI therapy during infections, and recovery occurred with appropriate treatment.

Concurrent use of TYSABRI in CD clinical trials with chronic steroids and/or methotrexate, 6-MP, and azathioprine did not result in an increase in overall infections compared to TYSABRI alone; however, the concomitant use of such agents could lead to an increased risk of serious infections.

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

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

Infusion-related Reactions An infusion-related reaction was defined in clinical trials as any adverse event occurring within two hours of the start of an infusion. In MS clinical trials, approximately 24% of TYSABRI-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebotreated patients. In the controlled CD clinical trials, infusion-related reactions occurred in approximately 11% of patients treated with TYSABRI compared to 7% of placebo-treated patients.

Reactions more common in the TYSABRI-treated MS patients compared to the placebo-treated MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving TYSABRI. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients [see Warnings and Precautions (5.5)]. All patients recovered with treatment and/or discontinuation of the infusion.

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

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

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

Patients in Study MS1 [see Clinical Studies (14.1)] were tested for antibodies to natalizumab every 12 weeks. The assays used were unable to detect low to moderate levels of antibodies to natalizumab. Approximately 9% of patients receiving TYSABRI developed detectable antibodies at

least once during treatment. Approximately 6% of patients had positive antibodies on more than one occasion. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.

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

Infusion-related reactions that were most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse reactions more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.

Patients in CD studies [see Clinical Studies (14.2)] were first tested for antibodies at Week 12, and in a substantial proportion of patients, this was the only test performed given the 12-week duration of placebo-controlled studies. Approximately 10% of patients were found to have antinatalizumab antibodies on at least one occasion. Five percent (5%) of patients had positive antibodies on more than one occasion. Persistent antibodies resulted in reduced efficacy and an increase in infusion-related reactions with symptoms that include urticaria, pruritus, nausea, flushing, and dyspnea.

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

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

Blood disorders: hemolytic anemia, thrombocytopenia (including immune thrombocytopenic purpura).

8.

USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of TYSABRI in pregnant women. In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose. These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals [see Data].

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

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

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

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

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

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

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

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

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

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

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

17.

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

General Counseling Information Counsel patients to understand the risks and benefits of TYSABRI before an initial prescription is written. The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescriber’s direction. INSTRUCT PATIENTS USING TYSABRI TO: • Read the Medication Guide before starting TYSABRI and before each TYSABRI infusion.

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

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

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

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

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

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

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

Immunosuppression/Infections Inform patients that TYSABRI may lower the ability of their immune system to fight infections.

Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection [see Warnings and Precautions (5.6)].

Thrombocytopenia Inform patients that Tysabri may cause a low platelet count, which can cause severe bleeding that may be life-threatening. Instruct patients to report any symptoms that may indicate thrombocytopenia, such as easy bruising, prolonged bleeding from cuts, petechiae, abnormally heavy menstrual periods, or bleeding from the nose or gums that is new [see Warnings and Precautions (5.8)].

TYSABRI (natalizumab) Manufactured by: Biogen Inc. Cambridge, MA 02142 USA US License No. 1697 © 2015-2020 Biogen Inc. All rights reserved.

06/2020 U.S. Patent Numbers: 5,840,299; 6,602,503

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Bristol Myers Squibb

Supernus Pharmaceuticals Inc.

Careers.AAN.com

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

San Diego Finest City Neurologist The Neuron Clinic—San Diego, California Private Premier Neurology Group in Beautiful Southern California - Thank you for taking the time to explore a career with us. At The Neuron Clinic we strive to help individuals, families, and communities with acute and chronic neurological conditions. As the fastest growing neurology practice group in Southern California, now is the perfect time to join our clinical team! We are actively looking to hire talented Neurologists who are passionate about patient care and committed to clinical excellence. Neurology fellowship trained subspecialties: dementia, movement disorders, EMG/neuromuscular, stroke and epilepsy would be especially welcome, though all interests can be supported in the context of General Neurology. Competitive salary with productivity bonus. A robust compensation and benefits package. Malpractice and professional expense stipends.

Clinical Research opportunities available. Flexible schedules and exceptional work/life balance. Collegial professional environment. Two-year partnership track. In Southern California, you’ll enjoy amazing recreational activities, spectacular natural sceneries, and an exceptional climate. Located 20 minutes of San Diego beaches, our communities offer outdoor and beach activities, great shopping, award winner school districts and an expanding variety of cultural opportunities. The quality of life in San Diego is hard to beat! We invite you to make a difference in the communities we serve. For additional information about this opportunity, please contact: Lena Bueno, Director: (951) 459-0067 or visit https://theneuronclinic.com Neurologist—Assistant/Associate Professor Central Vermont Medical Center—Vermont, Four Seasons of Outdoor Activities at Your Doorstep!

for the following: General Neurologist, Neurohospitalist, Vascular Neurologist, Interventionalist, and Movement Disorders.

Translating cutting edge research to world-class patient care is our highest priority. Our faculty are committed to providing and improving the most advanced therapies for neurological disorders. The Department has fostered the development of a wide range of subspecialty clinical services implementing advanced therapies based on groundbreaking research in areas such as Alzheimer's disease, Parkinson's disease, Muscular Dystrophy, deep brain stimulation, ataxia, epilepsy, multiple sclerosis, neuromuscular and sleep disorders, stroke, headache, pain management, and neurocritical care. We are committed to training our next generation of physicians through the training and development of 24 residents and approximately 12 fellows each year. University of Minnesota Physicians is based in the beautiful Minneapolis-St. Paul metropolitan area, consistently ranking as a best place to live—offering a high quality of life and low cost of living. Minneapolis/St. Paul boasts excellent school systems, a thriving workforce, award-winning culinary scene, museums of all types, outstanding theaters, and an international airport making travel easy. Please contact Rebecca Hughbanks at rhughban10@umphysicians.umn.edu with your CV or apply online at https://mphysicians.org/careers For more information regarding the Department of Neurology, please visit: https://med.umn.edu/neurology

the Green Mountain state, CVMC has a reputation for clinical excellence with a staff deeply rooted in our community. The general neurology practice sees a wide variety of neurologic conditions, including epilepsy/seizure disorders, stroke, chronic headaches/ migraines, multiple sclerosis, Parkinson’s and Alzheimer disease, as well as movement and neuromuscular disorders. The ideal candidate will be skilled in reading EEGs and/or conducting/interpreting EMGs. This is a full-time, 12-month, salaried position with attending staff privileges at CVMC. All applicants must be American Board of Psychiatry and Neurology board eligible/certified. Fellowship training in a clinical neurology discipline is desired, however not a requirement. Our goal is to continue the high level of clinical care and education currently provided as we develop our clinically integrated network. The Central Vermont Medical Center site is evolving as a graduate medical education site and opportunities for teaching will be supported. UVM is especially interested in candidates who can contribute to the diversity and excellence of the academic community through their research, teaching, and/or service. Applicants are requested to include in their cover letter information about how they will further this goal. UVM and UVM Medical Center are Equal Opportunity/Affirmative Action Employers. All qualified applicants will receive consideration for employment without regard to race, color, religion, sex, sexual orientation, gender identity, national origin, disability, protected veteran status, or any other category legally protected by federal or state law. The University encourages applications from all individuals who will contribute to the diversity and excellence of the institution. The application receipt and review process will begin immediately and continue until the position is filled. Interested individuals should apply online for position #45098 at www.uvmjobs.com. For more information, contact Sarah Child at Sarah.Child@CVMC. org or phone (802)225-1739. For more information regarding the Department of Neurological Sciences, please see our website at http://www.uvm.edu/medicine/neuro/

AANnews® Classified Advertising

he AAN offers a complete package of print, online, T and in-person recruitment advertising opportunities.

Visit careers.AAN.com for all AAN options, rates, and deadlines. d copy for the December 2021 print edition of A AANnews must be submitted by November 1, 2021.

The same deadline applies to changes/cancellations.

The Robert Larner, M.D. College of Medicine at the University of Vermont (UVM) and the University of Vermont Medical Center (UVMMC) seek to recruit a physician to join our established program in General/Comprehensive Neurology. The successful Neurology opportunities—University of Minnesota Physicians CHP: 21 Patient Reported Outcome Measures Ad—Half Page Horizontal> AN applicant will be involved in a primarily clinical care role at —Minneapolis/St. Paul area Placed in AANnews University of Vermont Health Network—Central Vermont The Department of Neurology at the University of Minnesota and 8.25 x 5.25Medical +0.125Center bleed,(CMVC) 4C in Berlin, Vermont. This position offers UMPhysicians is actively recruiting to grow our Neurology team the unique opportunity to work in a community setting while still of nearly 50 clinical faculty in 10 subspecialties. We are recruiting being involved with an academic center. Located in the heart of

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

Make Your Patient Your Partner Invest in the outcomes that matter most to your patients. Learn about common Patient Reported Outcome (PRO) scales and tools used in neurology at AAN.com/PRO.

AANnews • October 2021 37

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OCTOBER 1

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Application Deadline: 2022 AAN Research Program AAN.com/ResearchProgram

Deadline: UCNS 2021 Continuous Certification UCNS.org/C-cert

OCTOBER 11

NOVEMBER 5–7

Deadline: 2022 Annual Meeting Call for Abstracts AAN.com/22Abstracts

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Free Webinar: Tackling Structural Racism in Neurology Care https://bit.ly/3mKqx6B

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OCTOBER 18–22

Neurology Career Week Careers.AAN.com

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AAN Trainee Trivia AAN.com/traineetrivia

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NOVEMBER 23

Conclusion: Advanced Practice Provider Neurology Education Series AAN.com/APP

OCTOBER 20

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