2020 May AANnews

VOLUME 33 · ISSUE 5 · May 2020

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

GET FREE, DISCOUNTED ACCESS TO AAN EDUCATION RESOURCES Fulfill Your CME Needs The AAN is offering members free education resources and discounts to help neurologists maintain access to high-quality education products.

Free Annual Meeting On Demand and NeuroSAE 2019 Annual Meeting Edition Through spring 2021, the AAN is offering free access to 2019 Annual Meeting programming with Annual Meeting On Demand and has also revived the NeuroSAE Annual Meeting edition to help guide your study and self-assessment. To access, visit Learning.AAN.com and login with your AAN ID or associated email address.

2019 Annual Meeting on Demand Access the virtual library of sessions from the 2019 Annual Meeting in Philadelphia with 500 hours of content and over 240 hours of accredited content— and earn up to 242.75 AMA PRA Category 1 Credits®!

Continued on page 22

›

Reach the Practice Support Network Through practice @aan.com

Read New Practice Advisory on Thymectomy for Myasthenia Gravis

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

Staff experts respond within one business day and can seek the assistance of the Practice Support Network (PSN), a group of 20 practicing neurologists and graduates of AAN’s Practice Leadership Program for real-world expertise.

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

The AAN published “Practice Advisory: Thymectomy for Myasthenia Gravis (Practice Parameter Update)” in the March 25, 2020, online issue of Neurology ® and the April 21, 2020, print issue.

Continued on page 7

6

Race and Ethnicity Patient Data and the Axon Registry

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An operation to remove the thymus gland can help treat people with the main type of myasthenia gravis, known as generalized MG with AChR antibodies. Any invasive surgical procedure involves risk. However, thymectomy appears

21 Resident & Fellow Section of Neurology Seeks Research Articles

Continued on page 15

21 Revised Position Statement

Addresses Human Participants in Clinical Research

›

In Multiple

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AANnews · May 2020

May Highlights 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.

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

memberservices@aan.com

Website: AAN.com

Patent Foramen Ovale Practice Advisory Update Summary: Patent Foramen Ovale and Secondary Stroke Prevention and Secondary Stroke Prevention AAN Summary of Practice Advisory Update for Clinicians

This is afor summary of the American Academy of Neurology (AAN) “Practice Advisory Update Summary: Patent Foramen Ovale and Summary Patients Secondary Stroke Prevention” which was published in Neurology online on April 29, 2020, and appears in the May 19, 2020, print issue. and Their Families ®

Please refer to the full guideline on the AAN Guidelines web page for more information, including full descriptions of the processes for classifying evidence, deriving conclusions, and making recommendations.

What is the key message for me?  Recent studies have shown that for some patients, particularly those younger than 60 years who have had a stroke thought to be caused by a PFO, closure of the PFO reduces the risk of having another stroke better than medical treatments alone.  Before recommending a PFO closure in people who have had a stroke, it is important for doctors with expertise in stroke to rule out causes other than  There is a small risk of complication from PFO closure, including developing an abnormal heart rhythm. It is important that doctors and patients discuss these risks and benefits.

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

mechanisms, and secondary stroke prevention is optimized by targeting the most likely etiology of the preceding event.1-3 An appropriately thorough workup depends on the individual patient and whether a What is a PFO?

patent ovale (PFO) closure trialsthe all mandated A PFOforamen is a connection between right andthorough left evaluations for participants enrollment, angiography sides of the heart that before all babies haveincluding as they CT grow (CTA) or MR angiography (MRA) of the head and neck vessels in all in the and womb.

In most people, byinthe time they studies hypercoagulable screening many to rule out other reachmechanisms; adulthood,moreover, this connection closes transesophageal on its stroke all studies required echocardiography (TEE)in to four characterize thethe PFOconnection and ensure that it was own. In about one people, the mostopen. likely etiology for the initial event. There is accumulating stays

Level

Level B

cryptogenic stroke.4 Given they designed and initiated before A PFO presents a lowthat risk of were stroke.

Commonly,

having a PFO does not cause any problems.

However, in some cases, PFOs can contribute to strokes, and patients will<50 decide increasing ageand and isdoctors unlikely to occur in patients years. Other risk to insert a device to close this connection. This and may increase clinical includingthe systemic hypertension, prevents the flow of suspicion, blood between upper obesity, sleep of apnea, enlargedThis left atrium, hyperthyroidism, chambers the heart. procedure is knowndiabetes, alcohol abuse, cigarette smoking, elevated serum N-terminal pro b-type as a PFO closure. This procedure is done by using natriuretic peptide (NT-proBNP), frequent premature atrial contractions, 5,6 a catheter insert the closure device through the and increasedto P wave dispersion on ECG. blood vessels to the heart and does not typically PFO is highly prevalent, found in approximately 25% of the general require surgery. adult population on agitated-saline TEE and cadaveric studies.7,8

required prolonged monitoring before enrollment, although it is important

Level A

Level B

Transcranial Doppler ultrasonography (TCD) has been demonstrated

Low evidence = Future studies likely to change the conclusion

anatomic size, location, and length of the tunnel.9 and otherwise cryptogenic stroke, with increasing PFO prevalence in

younger patients stroke and those traditional vascular risk To with learn more, visit lacking AAN.com/guidelines Very low evidence = Future studies very likely to change the conclusion factors such as hypertension, hypercholesterolemia, and diabetes.10-12 The risk of stroke recurrence in patients with PFO and no other etiology

In patients being considered for PFO closure, clinicians should obtain complete vascular imaging (MRA or CTA) of the cervical and intracranial vessels to look for dissection, vasculopathy, and atherosclerosis.

In patients being considered for PFO closure, clinicians must Select patients being considered for PFO closure thought

shunting, although TCD does not rule out other cardioembolic sources

Moderate evidence = Future studies unlikely to change the conclusion

In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke, as was performed in all positive PFO closure trials.

distribution, assessing for an embolic pattern or a lacunar infarct (typically involving a single deep perforator, < 1.5 cm in diameter).

cardiac monitoring for at least 28 days. (Risk factors for obesity, sleep apnea, enlarged left atrium, elevated NT-proBNP, frequent premature atrial contractions, and increased P wave dispersion. Recently published guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society recommend prolonged ECG monitoring following cryptogenic stroke for patients older than 40 years, although more research is needed to with PFO.14)

Key to Evidence Levels morphology, including After the experts review all of the published research studies, they describe the strength ofPFO the evidence as follows: Strong evidence = Future studies

Recommendation

In patients being considered for PFO closure, clinicians Level B

Level B

15

Practice Advisory Update:

Experts from the American Academy of Neurology, or AAN, carefully reviewed the available evidence Recommendation 1 about secondary stroke prevention in patients with a patent foramen ovale, or PFO. The following Rationale summary highlights what their findings mean for you. Ischemic stroke may be caused by a variety of heterogeneous

5

In patients being considered for PFO closure, clinicians should assess for cardioembolic sources using transthoracic echocardiography (TTE) followed by TEE assessment if the Level B Studies should use bubble contrast, with and without Valsalva maneuver, to assess for right-to-left shunt and determine degree of shunting.

treated with medication alone. This stroke risk is generally lower than the stroke risk caused by other possible common stroke mechanisms.13 Thus, if an alternative plausible higher risk mechanism of stroke is

©2020 American Academy of Neurology

AAN.com

18

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

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

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

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

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

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

Check out APP Resources at AAN.com As more APPs enter the neurology workforce, onboarding resources and neuroanatomy education are necessary to successfully integrate them into practices. To help this be a smooth process, the AAN offers various resources in its APP Toolkit.

AAN’s Practice Advisory on PFO Is Updated The AAN’s new “Practice Advisory Update Summary: Patent Foramen Ovale and Secondary Stroke Prevention” was published in the April 29, 2020, online edition of Neurology ®.

Live Well, Lead Well Graduate Discovers Lasting Power of Community Since participating in the program, Rebecca MillerKuhlmann, MD, has implemented successful burnout-reduction strategies among residents and fellows within her own institution and has found inspiration and support in a strong—and ever growing—physician community.

News Briefs Free Telemedicine and COVID-19 Webinar

Federal Advocacy for Neurology and COVID-19

With more than 1,200 live participants on March 26 and 8,600 additional views on YouTube as of April 6, the AAN’s free Telemedicine and COVID-19 webinar updates members on best practices on implementing telemedicine services and updates on changing US regulations during the novel coronavirus public health emergency. As a companion to the webinar, the AAN published a Telemedicine FAQ with updated guidance on coding and regulation changes.

Additional telemedicine resources, including many for implementation, Medicare and Medicaid, state level, commercial payers, and more, are frequently updated on the AAN’s Telemedicine and Remote Care web page.

You can access the Academy’s resources via AAN.com/COVID19.

In March, the AAN sent a letter to Secretary of Health and Human Services Alex Azar outlining the AAN’s recommendations related to telehealth services and the response to COVID-19.

The AAN sent an additional letter to Vice President Mike Pence, chair of the White House Coronavirus Task Force, offering comprehensive recommendations to support patients and neurologists throughout the COVID-19 outbreak.

These letters already have yielded numerous positive outcomes for neurologists and neurology patients including actions to expand access to telehealth services, reimbursement for previously non-covered services, financial assistance for practices experiencing financial hardship, and reductions in administrative burdens. 

AANnews • May 2020 3

President’s Column

Providing Timely—and Inspiring—Communications During This Crisis I want to make sure you are aware that, because of the length of time it takes to print and mail AANnews®, our COVID-19 Neurology Resource Center web page at AAN.com/COVID19 and our weekly COVID-19 Neurology Resource Center Digest emailed to you each Saturday contain the timeliest information you can find on our responses to the pandemic and our continuing efforts to help you through this unprecedented period. I know you are extremely busy and consumed by the challenges you are facing, but I hope you will make a point of visiting AAN.com/COVID19 and reading our email updates as often as you possibly can.

We are painfully aware that some of our Academy members are being furloughed from their jobs and others have had hours and pay reduced.

Our Neurology Career Center at Careers.AAN.com now features a listing of employers in need of temporary, shortterm physician resources due to COVID-19 to help neurologists displaced due to clinic closures or other issues.

We have many neurology heroes amongst us, and I hope you join me in celebrating these incredible efforts during this time.

Recently, the AAN presented an important webinar on “Financial Support for Neurology Practices” where experts discussed opportunities and government assistance programs available to support your practice financially during the COVID-19 pandemic. Topics included the Small Business Paycheck Protection Program, Economic Injury Disaster Loan Program, Medicare advanced and accelerated payments, and more. The free, one-hour webinar was recorded, and you can find the link at AAN.com/COVID19.

Claire Clelland, MD, PhD, is collaborating with a Portland company to mass produce face shields and N95 masks. Their mask solution uses thermoform molding of plastic polyethylene terephthalate (PET) from recycled and decontaminated water bottles as the base Clelland material. Each face mask is formed in under 2.5 seconds from a mold and millions of pieces per day can be produced. Additional benefits include a clear plastic design that allows the mouth to be visible so users can communicate more clearly while wearing it, and an easy ability to self-check the seal for larger air leaks.

Stevens

In the midst of this crisis, there is some good news. The American Board of Psychiatry and Neurology (ABPN) has announced that the current Continuing Certification (CC) requirements have been deferred until December 31, 2021, though diplomates with certificates expiring in 2020 are not required to take a deferment and may still choose to sit for the CC/MOC exam or complete the pilot article assessments this year. For more information, please visit ABPN.com/coronavirus-covid-19-updates.

Some of the articles include: Not Enough N95 Masks? This Neurology Fellow Is Spearheading Development of a New Prototype,

by Orly Avitzur, MD, MBA, FAAN

With 3D Design Know-How, This Neurologist Is Working to Produce Face Shields, Gowns, Sanitizers for COVID-19,

by Orly Avitzur, MD, MBA, FAAN

Sarkar

Avitzur

Safdieh

Finally, I want to give a shout out to Neurology Today ® Editor-in-Chief Joseph E. Safdieh, MD, FAAN, and his staff for the inspiring and uplifting stories (two written by President Elect Orly Avitzur, MD, MBA, FAAN) of AAN members who have directed their attention to address shortages and challenges created by the current crisis.

4

AANnews • May 2020

Ochsner Health’s Korak Sarkar, MD, is leveraging the Ochsner Neurosciences medical 3D lab’s engineering and manufacturing expertise in combination with existing local materials and fabrication resources to help address the PPE needs, manufacturing more than 30,000 face shields

Tools & Resources

with the support of local businesses. They have created a disinfection process that uses an approach based on ultraviolet light that alleviates reliance on meager resources such as disinfection wipes, and they are working with local fashion and textile resources to produce thousands of barrier gowns.

COVID-19 Neurology Heroes: A Neurology Resident in Memphis—‘They Didn’t Have Anything to Tell Me,’

by Dan Hurley

Check out APP Resources at AAN.com The AAN’s Consortium of Neurology Advanced Practice Providers (CNAPP) consists of the more than 1,400 advanced practice provider (APP) members and serves as the audience and epicenter of APP initiatives and resources at the Academy.

As more APPs enter the neurology workforce, onboarding resources and neuroanatomy education are necessary to successfully integrate them into practices. To help this be a smooth process, the AAN offers various resources in its APP Toolkit, including: Online Neuroanatomy Animations Team-based Practice Dos & Don’ts Tipsheet Quick Reference for Physicians Working with APPs

Alexandrov

Malkoff

Krishnaiah

Thanks to the efforts of Neurology Program Chair Andrei V. Alexandrov, MD; Residency Program Director Marc Malkoff, MD, FAAN; and Associate Program Director Balaji Krishnaiah, MD, the residents at the University of Tennessee Health Science Center have been kept as safe as possible during the COVID-19 pandemic through use of telemedicine resources, and hospitals have developed explicit instructions on the need for proper PPE for all providers caring for patients.

Be sure to read these and more on the Neurology Today website at https://bit.ly/NT-COVID-19-Collection.

Times are exceedingly hard right now, but our ingenuity, spirit, and compassion are strong and through this strength we will persevere. As we bridge the distances—and differences—we endure today, we will move forward to a brighter tomorrow.

Your Academy is here for you, doing everything we can to keep you informed and prepared.

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

Patient FAQs about APPs CNAPP and other AAN committees and groups are developing additional educational materials for APP members and physician members working with APPs. To access the resources above and learn more about AAN’s offerings and opportunities for APPs and practicing neurologists, visit AAN.com/tools-and-resources/advanced-practice-providers. 

Tools & Resources

Race and Ethnicity Patient Data and the Axon Registry The AAN is committed to building and sustaining an inclusive organization that respects and values the diversity of our membership and the communities we serve. One way to improve is to collect more accurate race and ethnicity data at the patient level, as this data is required in order to perform analysis regarding patient disparities for neurologic conditions. For registry participants, the Axon Registry ® securely collects and analyzes outpatient encounter data from the electronic health records (EHRs) of their neurology patients. The AAN would like to see more of its US members join the Axon Registry to help more accurately capture race and ethnicity data for critical patient disparities analysis across the United States. The AAN’s Axon Registry is a qualified clinical data registry that was established in 2015 as a free member benefit to focus on quality improvement for neurology.

Race The US Census Bureau defines race as a person’s self-identification with one or more social groups.

Examples of races include White, Black or African American, Asian, American Indian and Alaska Native, Native Hawaiian.

Ethnicity Ethnicity is defined as an ethnic or social group that shares a common and distinctive culture, religion, or language. The US Office of Management and Budget (OMB) requires federal agencies to use a minimum of two ethnicities in collecting and reporting data: Hispanic or Latino and Not Hispanic or Latino. OMB defines "Hispanic or Latino" as a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin regardless of race. Examples of ethnic groups include, Argentinian, Colombian, Brazilian, Cuban, Puerto Rican, Venezuelan.

Race and Ethnicity Data in the Axon Registry In 2017, the AAN partnered with IQVIA to perform an external validation of the Axon Registry data. As part of that data validation, it found a 100-percent match for ethnicity between the Axon Registry and the EHRs ethnicity. For race, there was an 88-percent match between the Axon Registry and the EHRs. This 12-percent mismatch resulted from the ethnicity being entered as race within practice EHRs. Opportunity exists for neurology to improve.

Currently, over 28 percent of patients in the Axon Registry’s data file identify their race as unknown. For ethnicity, the unknown percentage increases to over 32 percent of Axon Registry patients. The classification of unknown is due to selecting ‘other,’ selecting nothing, or the mapping of non-race or non-ethnicity options. Missing, unknown, or not detailed race and ethnicity may lead to underrepresentation of populations in data analyses and in quality improvement efforts.

Moving Forward In 2017, the AAN Board of Directors created the Health Care Disparities Task Force, chaired by Brett M. Kissela, MD, MS, FAHA, FAAN. One of the objectives the task force concluded with was “Improve data available (in Axon Registry and AAN’s member-database) to assess disparities in care in a

6

AANnews • May 2020

meaningful way.” Kissela said, “We know there are disparities in neurology care by race and ethnicity, and with accurate and complete race and ethnicity in the Axon Registry we can work to close these disparity gaps.”

With the current status of classification for race and ethnicity in the Axon Registry, it is difficult to address inclusiveness of the data or how representative is. It is important to make sure that we are educating all neurologists, and Axon Registry participants in particular, to enter accurate and complete patient race and ethnicity and that neurologists understand how the information entered into the EHR patient medical record ultimately impacts how we can analyze the data for the benefit of the neurology community.

The high-level race and ethnicity categories listed above from the OMB currently being used in many EHRs may be suitable for the statistical or epidemiologic or public health reporting purposes for which they were developed but may not be adequate in the pursuit of precision medicine and enhancing therapy or clinical decisions (Health IT.gov). There is movement to specify race and ethnicity to a greater degree. In March 2020, the CDC announced extended classifications for race and ethnicity. The extended classifications will provide more detailed information regarding race and ethnicity. Richard T. Benson, MD, PhD, of the National Institute of Neurological Disorders and Stroke said “race and ethnic disparities in neurological care exist. More accurate and detailed information on race and ethnicity may help medical providers better understand and eliminate inequities based on these social constructs.”

The neurology community needs accurate and complete race and ethnicity details in patient medical records. As we close the gap of unknown race and ethnicity in the Axon Registry, we can start to close some of the neurology disparities that exist. In additional to the benefits to collecting more detailed information regarding of race and ethnicity, there is also movement to create standards to define patient gender more fully. Collecting sexual orientation and gender identity (SOGI) information will also lead to closing more of the neurology disparities that exist.

For more information about joining the Axon Registry and enrollment, visit AAN.com/view/Axon. 

Reach the Practice Support Network Through practice @aan.com continued from cover

PRACTICE MANAGEMENT

Q: I am looking to implement telemedicine services.

Where should I start?

A: Regulations surrounding telehealth services continue to be confusing. The time spent navigating the policies can be a barrier from even beginning to provide the services.

The AAN is staying on top of changing regulations and has curated a multitude of resources to help you navigate the shifting landscape. Visit our telehealth website to find an implementation guide, resources on payer coverage and reimbursement, and updates on the AAN’s advocacy efforts to ensure patients who want remote services have access and neurologists receive fair reimbursement for their quality care. Learn more at AAN.com/telehealth.

CODING

Q: Can I report 95718 or 95720 for a multi-day ambulatory VEEG if I receive a download of the VEEG data every 24 hours instead of a single download at the end of the ambulatory study?

A: N o, it would not be appropriate to report either code for ambulatory studies >24 hours. 95717–95720 are intended for long-term EEG monitoring services where the physician has access to the EEG data throughout the duration of the recording (intended to guide interventions or alterations in care during the recording period, as is typical for inpatient studies) and generates a daily report for each 24-hour segment of the recording with a summary report at the conclusion of the multiday studies. If these requirements are not met, the correct code for the professional component would be 95721–95726.

Q: Can professional code 95718 VEEG, 2–12 hours be billed at either the beginning or ending of a multiple-day study if it is used only once? This would be when there are daily reports, but the first report falls within the 2–12-hour period.

A. No, 95718 should only be reported at the conclusion of a study. Count time continuously from the start of recording.

For a multi-day study, the first 24-hour period of 95720 will end during the second calendar day. If the final day includes more than 2 hours beyond a 24-hour period, then use 95718 for that final recording day spanning between 2-12 hours.

QUALITY PAYMENT PROGRAM (QPP)

Q: Is there a neurology Patient-centered Medical Home or neurology Alternative Payment Model?

A: C urrently, there is not a neurology-specific Patient-centered Medical Home (PCMH) or other Alternative Payment Model (APM) specific to neurology available widely or within the QPP. However, several neurology practices have pursued the Patientcentered Specialty Practice (PCSP) designation through the National Committee for Quality Assurance (NCQA), which builds off the PCMH concept and fosters care coordination between specialists and primary care practices. If this is a program neurology practices are interested in, they should reach out to NCQA directly to discuss pursuing implementation of the PCSP designation for their practice. Please note, the PCSP designation is not considered an Advanced APM in the QPP but does employ many of the principles of APMs. For questions specific to your practice’s participation in QPP or value-based care models, contact practice @aan.com and staff can help direct you to the AAN’s Value-based Care and Quality Payment Program resources that address your question. 

AI Tool as Diagnostic Aid Among Intriguing Topics in New Neurology: Clinical Practice The April/May issue of Neurology® Clinical Practice offers an array of articles of interest to practicing neurologists.

“Machine Learning as a Diagnostic Decision Aid for Patients with Transient Loss of Consciousness” investigated the feasibility of using an artificial intelligence tool to distinguish reliably between syncope, epilepsy, and psychogenic non-epileptic seizures in patients presenting with transient loss of consciousness.

A peer-reviewed

“Worldwide Survey of Neurologists on Approach to Autoimmune

Encephalitis” examines data from 1,333 respondents from 94 countries on case-based scenarios about a patient with suspected autoimmune encephalitis (AE).

Results showed that neuroimmunologists and those treating more patients with AE generally took a more proactive approach to testing and immunotherapy than their peers. The survey results also r 2, April 2020

Volume 10, Numbe

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RESEARCH

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RESEARCH

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RESEARCH

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identified considerable heterogeneity in the diagnosis and management of AE. Additional articles discuss health services interventions to optimize resource utilization and improve patient outcomes, including “Cerebral Venous Thrombosis Associations Between Disease Severity and Cardiac Markers,” a study evaluating hospital readmissions for patients hospitalized for seizures.

Neurology: Clinical Practice, published six times a year, is available in print (for US members only), online, and for the iPad and Android. Visit Neurology.org/cp for more information. 

For adults.

Not actual patients.

INDICATION MAYZENT® (siponimod) 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 • Patients with a CYP2C9*3/*3 genotype • In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure • Presence of Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome, unless patient has a functioning pacemaker Infections: MAYZENT may increase risk of infections with some that are serious in nature. Life-threatening and rare fatal infections have occurred.

Before starting MAYZENT, review a recent complete blood count (CBC) (ie, within 6 months or after discontinuation of prior therapy). Delay initiation of treatment in patients with severe active infections until resolved. Employ effective treatments and monitor patients with symptoms of infection while on therapy. Consider discontinuing treatment if patient develops a serious infection.

Cases of fatal cryptococcal meningitis (CM) were

reported in patients treated with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have occurred with MAYZENT. If CM is suspected, MAYZENT should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

No cases of progressive multifocal leukoencephalopathy (PML) were reported in MAYZENT clinical trials; however, they have been observed in patients treated with another sphingosine 1-phosphate (S1P) receptor modulator and other multiple sclerosis (MS) therapies. If PML is suspected, MAYZENT should be discontinued.

Cases of herpes viral infection, including one case of reactivation of varicella zoster virus leading to varicella zoster meningitis, have been reported.

Patients without a confirmed history of varicella zoster virus (VZV) or without vaccination should be tested for antibodies before starting MAYZENT. If VZV antibodies are not present or detected, then VZV immunization is recommended and MAYZENT should be initiated 4 weeks after vaccination.

Use of live vaccines should be avoided while taking MAYZENT and for 4 weeks after stopping treatment.

Caution should be used when combining treatment (ie, anti-neoplastic, immune-modulating, or immunosuppressive therapies) due to additive immune system effects.

FOR PATIENTS WITH FIRST SIGNS OF PROGRESSION IN RMS1

STAY AHEAD OF

PROGRESSION WITH MAYZENT ® (siponimod) MAYZENT IS

THE FIRST AND ONLY oral DMT studied and proven to delay disability progression in a more progressed patient population in RMS (mean EDSS score of 5.4)1-3

THE

DUAL MOA

OF MAYZENT

targets S1P1,5—2 key receptors thought to play a role in RMS inflammation and neurodegeneration.

Works in the periphery to limit active lymphocytes from leaving the lymph nodes, which may reduce lymphocyte migration into the CNS1,4-7

MAYZENT DEMONSTRATED

SAFETY

in the largest trial designed for this more progressed patient population in RMS1,3,8

The mechanism by which siponimod exerts therapeutic effects on MS is unknown.1 CNS=central nervous system; DMT=disease-modifying therapy; EDSS=Expanded Disability Status Scale; MOA=mechanism of action; MS=multiple sclerosis; RMS=relapsing MS.

LEARN ABOUT THE SIGNS OF PROGRESSION

mayzenthcp.com

IMPORTANT SAFETY INFORMATION (CONT) Macular Edema: In most cases, macular edema occurred within 4 months of therapy. Patients with history of uveitis or diabetes are at an increased risk.

Before starting treatment, an ophthalmic evaluation of the fundus, including the macula, is recommended and at any time if there is a change in vision. The use of MAYZENT in patients with macular edema has not been evaluated; the potential risks and benefits to the

individual patient should be considered.

Bradyarrhythmia and Atrioventricular Conduction Delays: Prior to initiation of MAYZENT, an ECG should be obtained to determine if preexisting cardiac conduction abnormalities are present. In all patients, a dose titration is recommended for initiation of MAYZENT treatment to help reduce cardiac effects.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

IMPORTANT SAFETY INFORMATION (CONT) Bradyarrhythmia and Atrioventricular Conduction Delays (cont): MAYZENT was not studied in patients who had: • In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization • New York Heart Association Class II-IV heart failure • Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second-degree AV-block or higher-grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker • Significant QT prolongation (QTc greater than 500 msec) • Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs Reinitiation of treatment (initial dose titration, monitoring effects on heart rate and AV conduction [ie, ECG]) should apply if ≥4 consecutive daily doses are missed.

Respiratory Effects: MAYZENT may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy if clinically warranted.

Liver Injury: Elevation of transaminases may occur in patients taking MAYZENT. Before starting treatment, obtain liver transaminase and bilirubin levels. Closely monitor patients with severe hepatic impairment.

Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked, and MAYZENT should be discontinued if significant liver injury is confirmed.

Increased Blood Pressure: Increase in systolic and diastolic pressure was observed about 1 month after initiation of treatment and persisted with continued treatment. During therapy, blood pressure should be monitored and managed appropriately.

Fetal Risk: Based on animal studies, MAYZENT may cause fetal harm. Women of childbearing

potential should use effective contraception to avoid pregnancy during and for 10 days after stopping MAYZENT therapy.

Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for patients treated with MAYZENT in clinical trials. If patients develop any unexpected neurological or psychiatric symptoms, a prompt evaluation should be considered. If PRES is suspected, MAYZENT should be discontinued.

Unintended Additive Immunosuppressive Effects From Prior Treatment or After Stopping MAYZENT: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects.

Initiating treatment with MAYZENT after treatment with alemtuzumab is not recommended.

After stopping MAYZENT therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.

Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy.

However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore, caution should be applied 3-4 weeks after the last dose of MAYZENT. Severe Increase in Disability After Stopping MAYZENT: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of an S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping MAYZENT treatment, thus patients should be monitored upon discontinuation.

Most Common Adverse Reactions: Most common adverse reactions (>10%) are headache, hypertension, and transaminase increases.

Please see additional Important Safety Information on the previous pages, and Brief Summary of full Prescribing Information on adjacent pages.

References: 1. Mayzent [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 2019. 2. Data on file.

First and only progressing RMS treatment. Novartis Pharmaceuticals Corp; January 2020. 3. Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. 4. O’Sullivan C, Schubart A, Mir AK, Dev KK. The dual S1PR1/S1PR5 drug BAF312 (siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation. 2016;13:31. 5. Gergely P, NuessleinHildesheim B, Guerini D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012;167(5):1035-1037. 6. Mannioui A, Vauzanges Q, Fini JB, et al. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination. Mult Scler. 2018;24(11): 1421-1432. 7. Choi JW, Chun J. Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta. 2013;1831(1):20-32. 8. New Novartis analyses at AAN show siponimod’s efficacy on disability and cognition in secondary progressive MS patients. Novartis Pharmaceuticals Corporation website. https://www.novartis.com/news/media-releases/new-novartis-analyses-aan-show-siponimods-efficacy-disability-and-cognitionsecondary-progressive-ms-patients. Published April 20, 2018. Accessed February 4, 2020.

MAYZENT and the MAYZENT logo are registered trademarks of Novartis AG.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2020 Novartis

3/20

MZT-1386605

MAYZENT® (siponimod) tablets, for oral use Initial U.S. Approval: 2019 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE MAYZENT 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.

4 CONTRAINDICATIONS MAYZENT is contraindicated in patients who have: • A CYP2C9*3/*3 genotype [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.5) in the full prescribing information] • In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure • Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Infections Risk of Infections MAYZENT causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. MAYZENT may therefore increase the risk of infections, some serious in nature [see Clinical Pharmacology (12.2) in the full prescribing information]. Life-threatening and rare fatal infections have occurred in association with MAYZENT. In Study 1 [see Clinical Studies (14) in the full prescribing information], the overall rate of infections was comparable between the MAYZENTtreated patients and those on placebo (49.0% vs. 49.1% respectively).

However, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection, and fungal skin infection were more common in MAYZENT-treated patients. In Study 1, serious infections occurred at a rate of 2.9% in MAYZENT-treated patients compared to 2.5% of patients receiving placebo.

Before initiating treatment with MAYZENT, results from a recent complete blood count (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed.

Initiation of treatment with MAYZENT should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after discontinuation of MAYZENT, vigilance for infection should be continued throughout this period [see Warnings and Precautions (5.11)].

Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with MAYZENT should be considered if a patient develops a serious infection.

Cryptococcal Infections Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have also occurred with MAYZENT. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment.

MAYZENT treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Herpes Viral Infections Cases of herpes viral infection, including one case of reactivation of VZV infection leading to varicella zoster meningitis, have been reported in the development program of MAYZENT. In Study 1, the rate of herpetic infections was 4.6% in MAYZENT-treated patients compared to 3.0% of patients receiving placebo. In Study 1, an increase in the rate of herpes zoster infections was reported in 2.5% of MAYZENT-treated patients compared to 0.7% of patients receiving placebo. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating MAYZENT (see Vaccinations below).

Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (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. 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.

No cases of PML have been reported in MAYZENT-treated patients in the development program; however, PML has been reported in patients treated with a S1P receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with MAYZENT should be suspended until PML has been excluded.

Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be coadministered with caution because of the risk of additive immune system effects during such therapy [see Drug Interactions (7.1)].

Vaccinations Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating MAYZENT treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with MAYZENT, following which initiation of treatment with MAYZENT should be postponed for 4 weeks to allow the full effect of vaccination to occur.

The use of live attenuated vaccines should be avoided while patients are taking MAYZENT and for 4 weeks after stopping treatment [see Drug Interactions (7.1)].

Vaccinations may be less effective if administered during MAYZENT treatment. MAYZENT treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended.

5.2 Macular Edema Macular edema was reported in 1.8% of MAYZENT-treated patients compared to 0.2% of patients receiving placebo. The majority of cases occurred within the first four months of therapy.

An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and at any time if there is any change in vision while taking MAYZENT. Continuation of MAYZENT therapy in patients with macular edema has not been evaluated. A decision on whether or not MAYZENT should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during MAYZENT therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the clinical trial experience in adult patients with all doses of MAYZENT, the rate of macular edema was approximately 10% in MS patients with a history of uveitis or diabetes mellitus versus 2% in those without a history of these diseases. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.

5.3 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of MAYZENT treatment results in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of MAYZENT [see Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.2) in the full prescribing information].

MAYZENT was not studied in patients who had: • In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization • New York Heart Association Class II-IV heart failure • Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second degree AV-block or higher grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker • Significant QT prolongation (QTc greater than 500 msec) • Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs [see Drug Interactions (7.2)] Reduction in Heart Rate After the first titration dose of MAYZENT, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are

seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation.

In Study 1, bradycardia occurred in 4.4% of MAYZENT-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention [see Adverse Reactions (6.1)]. Heart rates below 40 bpm were rarely observed.

Atrioventricular Conduction Delays Initiation of MAYZENT treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of MAYZENTtreated patients and in 1.9% of patients receiving placebo in Study 1.

Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with MAYZENT in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation of MAYZENT treatment.

If treatment with MAYZENT is considered, advice from a cardiologist should be sought: • In patients with significant QT prolongation (QTc greater than 500 msec) • In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs [see Drug Interactions (7.2)] • In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • In patients with a history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block [see Contraindications (4)] Treatment-Initiation Recommendations • Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.

• In all patients, a dose titration is recommended for initiation of MAYZENT treatment to help reduce cardiac effects [see Dosage and Administration (2.2, 2.3) in the full prescribing information].

• In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first-dose monitoring is recommended [see Dosage and Administration (2.1, 2.4) in the full prescribing information].

• Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, MAYZENT is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.

• Use of MAYZENT in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.

• Experience with MAYZENT is limited in patients receiving concurrent therapy with drugs that decrease heart-rate (e.g., beta-blockers, calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate, such as ivabradine and digoxin). Concomitant use of these drugs during MAYZENT initiation may be associated with severe bradycardia and heart block.

• For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing MAYZENT treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, MAYZENT can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm.

Treatment with MAYZENT can then be initiated and treatment with a beta-blocker can be reinitiated after MAYZENT has been up-titrated to the target maintenance dosage [see Drug Interactions (7.3)].

• For patients taking other drugs that decrease heart rate, treatment with MAYZENT should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate [see Dosage and Administration (2.4) in the full prescribing information and Drug Interactions (7.2)].

Missed Dose During Treatment Initiation and Reinitiation of Therapy Following Interruption If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations [see Dosage and Administration (2.2, 2.3) in the full prescribing information].

5.4 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in MAYZENT-treated patients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline in absolute FEV1 from baseline compared to placebo was 88 mL [95% confidence interval (CI): 139, 37] at 2 years. The mean difference between MAYZENT-treated patients and patients receiving placebo in percent predicted FEV1 at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. In Study 1, five patients discontinued MAYZENT because of decreases in pulmonary function testing. MAYZENT has been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary disease. The changes in FEV1 were similar in this subgroup compared with the overall population. Spirometric evaluation of respiratory function should be performed during therapy with MAYZENT if clinically indicated.

5.5 Liver Injury Elevations of transaminases may occur in MAYZENT-treated patients.

Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of MAYZENT therapy.

In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of MAYZENT-treated patients compared to 3.7% of patients receiving placebo, mainly because of transaminase [alanine aminotransferase/aspartate aminotransferase/gamma-glutamyltransferase (ALT/AST/GGT)] elevations.

In Study 1, ALT or AST increased to three and five times the upper limit of normal (ULN) in 5.6% and 1.4% of MAYZENT-treated patients, respectively, compared to 1.5% and 0.5% of patients receiving placebo, respectively. ALT or AST increased eight and ten times ULN in MAYZENTtreated patients (0.5% and 0.2%, respectively) compared to no patients receiving placebo. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of MAYZENT. In clinical trials, MAYZENT was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have liver enzymes checked. MAYZENT should be discontinued if significant liver injury is confirmed.

Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking MAYZENT, caution should be exercised when using MAYZENT in patients with a history of significant liver disease.

5.6 Increased Blood Pressure In Study 1, MAYZENT-treated patients had an average increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg in diastolic pressure, which was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. Hypertension was reported as an adverse reaction in 12.5% of MAYZENT-treated patients and in 9.2% of patients receiving placebo. Blood pressure should be monitored during treatment with MAYZENT and managed appropriately.

5.7 Fetal Risk Based on animal studies, MAYZENT may cause fetal harm [see Use in Specific Populations (8.1)]. Because it takes approximately 10 days to eliminate MAYZENT from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping MAYZENT treatment.

5.8 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for MAYZENT-treated patients in the development program. However, should a MAYZENTtreated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical

visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider a MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, MAYZENT should be discontinued.

5.9 Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating MAYZENT. Initiating treatment with MAYZENT after treatment with alemtuzumab is not recommended [see Drug Interactions (7.1)].

5.10 Severe Increase in Disability After Stopping MAYZENT Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping MAYZENT treatment. Patients should be observed for a severe increase in disability upon MAYZENT discontinuation and appropriate treatment should be instituted, as required.

5.11 Immune System Effects After Stopping MAYZENT After stopping MAYZENT therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.

Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy [see Clinical Pharmacology (12.2) in the full prescribing information]. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied 3-4 weeks after the last dose of MAYZENT [see Drug Interactions (7.1)].

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: • Infections [see Warnings and Precautions (5.1)] • Macular Edema [see Warnings and Precautions (5.2)] • Bradyarrhytmia and Atrioventricular (AV) Conduction Delays [see Warnings and Precautions (5.3)] • Respiratory Effects [see Warnings and Precautions (5.4)] • Liver Injury [see Warnings and Precautions (5.5)] • Increased Blood Pressure [see Warnings and Precautions (5.6)] • Fetal Risk [see Warnings and Precautions (5.7)] • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8)] • Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies [see Warnings and Precautions (5.9)] • Severe Increase in Disability After Stopping MAYZENT [see Warnings and Precautions (5.10)] • Immune System Effects After Stopping MAYZENT [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions 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.

A total of 1737 MS patients have received MAYZENT at doses of at least 2 mg daily. These patients were included in Study 1 [see Clinical Studies (14) in the full prescribing information] and in a Phase 2 placebocontrolled study in patients with MS. In Study 1, 67% of MAYZENT-treated patients completed the double-blind part of the study, compared to 59.0% of patients receiving placebo. Adverse events led to discontinuation of treatment in 8.5% of MAYZENT-treated patients, compared to 5.1% of patients receiving placebo. The most common adverse reactions (incidence at least 10%) in MAYZENT-treated patients in Study 1 were headache, hypertension, and transaminase increases.

Table 3 lists adverse reactions that occurred in at least 5% of MAYZENTtreated patients and at a rate at least 1% higher than in patients receiving placebo.

Table 3 Adverse Reactions Reported in Study 1 (Occurring in at Least 5% of MAYZENT-Treated Patients and at a Rate at Least 1% Higher Than in Patients Receiving Placebo) Adverse Reaction Headachea Hypertensionb Transaminase increasedc Falls Edema peripherald Nausea Dizziness Diarrhea Bradycardiae Pain in extremityf

MAYZENT 2 mg (N = 1099) %

Placebo (N = 546) %

15 13 11 11 8 7 7 6 6 6

14 9 3 10 4 4 5 4 3 4

Terms were combined as follows: tension headache, sinus headache, cervicogenic headache, drug withdrawal headache, and procedural headache. bhypertension, blood pressure increased, blood pressure systolic increased, essential hypertension, blood pressure diastolic increased. calanine aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, liver function test increased, hepatic function abnormal, liver function test abnormal, transaminases increased. dedema peripheral, joint swelling, fluid retention, swelling face. ebradycardia, sinus bradycardia, heart rate decreased. fpain in extremity and limb discomfort. aheadache,

The following adverse reactions have occurred in less than 5% of MAYZENT-treated patients but at a rate at least 1% higher than in patients receiving placebo: herpes zoster, lymphopenia, seizure, tremor, macular edema, AV block (1st and 2nd degree), asthenia, and pulmonary function test decreased [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

Seizures In Study 1, cases of seizures were reported in 1.7% of MAYZENT-treated patients, compared to 0.4% in patients receiving placebo. It is not known whether these events were related to the effects of MS, to MAYZENT, or to a combination of both.

Respiratory Effects Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with MAYZENT [see Warnings and Precautions (5.4)].

Vascular Events Vascular events, including ischemic strokes, pulmonary embolisms, and myocardial infarctions, were reported in 3.0% of MAYZENT-treated patients compared to 2.6% of patients receiving placebo. Some of these events were fatal. Physicians and patients should remain alert for the development of vascular events throughout treatment, even in the absence of previous vascular symptoms. Patients should be informed about the symptoms of cardiac or cerebral ischemia caused by vascular events and the steps to take if they occur.

Malignancies Malignancies such as malignant melanoma in situ and seminoma were reported in MAYZENT-treated patients in Study 1. An increased risk of cutaneous malignancies has been reported in association with another S1P modulator.

7 DRUG INTERACTIONS 7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies MAYZENT has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1)].

When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.9)].

Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with MAYZENT after alemtuzumab is not recommended.

MAYZENT can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.

7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate MAYZENT has not been studied in patients taking QT prolonging drugs.

Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with MAYZENT is considered, advice from a cardiologist should be sought.

Because of the potential additive effects on heart rate, treatment with MAYZENT should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., ivabradine, digoxin) [see Warnings and Precautions (5.3) and Drug Interactions (7.3)]. If treatment with MAYZENT is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.

7.3 Beta-Blockers Caution should be applied when MAYZENT is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of MAYZENT [see Warnings and Precautions (5.3)]. Beta-blocker treatment can be initiated in patients receiving stable doses of MAYZENT [see Clinical Pharmacology (12.2) in the full prescribing information].

7.4 Vaccination During and for up to one month after discontinuation of treatment with MAYZENT, vaccinations may be less effective; therefore MAYZENT treatment should be paused 1 week prior and for 4 weeks after vaccination [see Warnings and Precautions (5.1)].

The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during MAYZENT treatment and for up to 4 weeks after discontinuation of treatment with MAYZENT [see Warnings and Precautions (5.1)].

7.5 CYP2C9 and CYP3A4 Inhibitors Because of a significant increase in exposure to siponimod, concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate - moderate or strong CYP3A4 inhibitor.

Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inhibitors.

7.6 CYP2C9 and CYP3A4 Inducers Because of a significant decrease in siponimod exposure, concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and strong CYP3A4 induction is not recommended for all patients. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducer (e.g., rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer.

Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inducers.

Concomitant use of MAYZENT and moderate (e.g., modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype [see Clinical Pharmacology (12.3) in the full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of MAYZENT in pregnant women. Based on animal data and its mechanism of action, MAYZENT can cause fetal harm when administered to a pregnant woman (see Data). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated MAYZENT-induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats.

Increased incidences of post-implantation loss and fetal abnormalities (external, urogenital and skeletal) in rat and of embryo-fetal deaths, abortions and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day.

In the US 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 When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, post implantation loss and fetal malformations (visceral and skeletal) were increased at the lowest

dose tested, the only dose with fetuses available for evaluation.

A no-effect dose for adverse effects on embryo-fetal development in rats was not identified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at the recommended human dose (RHD) of 2 mg/day.

When siponimod (0, 0.1, 1, or 5 mg/kg) was orally administered to pregnant rabbits during the period of organogenesis, embryolethality and increased incidences of fetal skeletal variations were observed at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose (0.1 mg/kg) for adverse effects on embryo-fetal development in rabbits is less that than in humans at the RHD. When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally administered to female rats throughout pregnancy and lactation, increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring at all but the lowest dose tested. An increase in malformations was observed at all doses. A no-effect dose for adverse effects on pre- and postnatal development in rats was not identified. The lowest dose tested (0.05 mg/kg) is less than the RHD, on a mg/m2 basis.

8.2 Lactation Risk Summary There are no data on the presence of siponimod in human milk, the effects of MAYZENT on the breastfed infant, or the effects of the drug on milk production. A study in lactating rats has shown excretion of siponimod and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the motherâ&#x20AC;&#x2122;s clinical need for MAYZENT and any potential adverse effects on the breastfed infant from MAYZENT or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Females Before initiation of MAYZENT treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with MAYZENT [see Use in Specific Populations (8.1)]. Since it takes approximately 10 days to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period [see Warnings and Precautions (5.7)].

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

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

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 CYP2C9 Genotype Before initiation of treatment with MAYZENT, test patients to determine CYP2C9 genotype. MAYZENT is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype), which is approximately 0.4%-0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. MAYZENT dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod [see Dosage and Administration (2.3) and Clinical Pharmacology (12.5) in the full prescribing information].

10 OVERDOSAGE In patients with overdosage of MAYZENT, it is important to observe for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.2) in the full prescribing information].

There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body. The decrease in heart rate induced by MAYZENT can be reversed by atropine or isoprenaline.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 MAYZENT is a registered trademark of Novartis AG Š Novartis T2019-45

Policy & Guidelines

AAN’s Practice Advisory on PFO Is Updated The AAN’s new “Practice Advisory Update Summary: Patent Foramen Ovale and Secondary Stroke Prevention” was published in the April 29, 2020, online edition of Neurology ®.

According to the advisory, recent studies have shown that for some patients, particularly those younger than 60 years, who have had a stroke thought to be caused by a PFO, closure of the a PFO reduces the risk of having another stroke better than medical treatments alone. However, before recommending a PFO closure in people who have had a stroke, it is important for doctors with expertise in stroke to rule out causes other than the PFO. There is a small risk of complication from PFO closure, including developing an abnormal heart rhythm.

It is important that doctors and patients discuss these risks and benefits.

Read the guideline and access summaries for clinicians and families/caregivers and a slide presentation set at AAN.com/PFO. For more information, email guidelines@aan.com or call (612) 928-6056. 

Practice Advisory Update:

Patent Foramen Ovale and Secondary Stroke Prevention Summary for Patients and Their Families Experts from the American Academy of Neurology, or AAN, carefully reviewed the available evidence about secondary stroke prevention in patients with a patent foramen ovale, or PFO. The following summary highlights what their findings mean for you.

What is the key message for me?  Recent studies have shown that for some patients, particularly those younger than 60 years who have had a stroke thought to be caused by a PFO, closure of the PFO reduces the risk of having another stroke better than medical treatments alone.  Before recommending a PFO closure in people who have had a stroke, it is important for doctors with expertise in stroke to rule out causes other than  There is a small risk of complication from PFO closure, including developing an abnormal heart rhythm. It is important that doctors and patients discuss these risks and benefits.

AAN Summary of Practice Advisory Update for Clinicians

Practice Advisory Update Summary: Patent Foramen Ovale and Secondary Stroke Prevention

What is a PFO? A PFO is a connection between the right and left sides of the heart that haveofas grow Academy of Neurology (AAN) “Practice Advisory Update Summary: Patent Foramen Ovale and Thisallisbabies a summary thethey American Stroke Prevention” in the womb. In mostSecondary people, by the time they which was published in Neurology ® online on April 29, 2020, and appears in the May 19, 2020, print issue. reach adulthood, this connection closes on its Please refer to the full guideline on the AAN Guidelines web page for more information, including full descriptions of the processes for own. In about one in four people, the connection classifying evidence, deriving conclusions, and making recommendations. stays open.

A PFO presents a low risk of stroke. Commonly, Recommendation 1 having a PFO does not cause any problems.

Rationale However, in some cases, PFOs can Ischemic stroke maycontribute be caused by a variety of heterogeneous to strokes, and doctors and patients will decide mechanisms, and secondary stroke prevention is optimized by targeting most likely etiology of the preceding event.1-3 An appropriately to insert a device to the close this connection.

This workup depends on the individual patient and whether a prevents the flow of thorough blood between the upper chambers of the heart. This procedure is known patent foramen ovale (PFO) closure trials all mandated thorough as a PFO closure. This procedure is done by using evaluations for participants before enrollment, including CT angiography a catheter to insert the device through (CTA)closure or MR angiography (MRA) ofthe the head and neck vessels in all screening in many to rule out other blood vessels to thestudies heart and andhypercoagulable does not typically require surgery. stroke mechanisms; moreover, all studies required transesophageal echocardiography (TEE) to characterize the PFO and ensure that it was the most likely etiology for the initial event. There is accumulating

Level

Recommendation

Level B

In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke, as was performed in all positive PFO closure trials.

In patients being considered for PFO closure, clinicians

Level B

Level B

cryptogenic stroke.4 Given that they were designed and initiated before Key to Evidence Levels After the experts review all of the published research studies, they describe the strength of the evidence as follows: Strong evidence = Future studies

Low evidence = Future studies likely to change the conclusion

Moderate evidence = Future studies unlikely to change the conclusion

Very low evidence = Future studies very likely to change the conclusion

required prolonged monitoring before enrollment, although it is important

Level A

distribution, assessing for an embolic pattern or a lacunar infarct (typically involving a single deep perforator, < 1.5 cm in diameter).

In patients being considered for PFO closure, clinicians should obtain complete vascular imaging (MRA or CTA) of the cervical and intracranial vessels to look for dissection, vasculopathy, and atherosclerosis.

In patients being considered for PFO closure, clinicians must

increasing age and is unlikely to occur in patients <50 years. Other risk

Select patients being considered for PFO closure thought

and may increase clinical suspicion, including systemic hypertension, obesity, sleep apnea, enlarged left atrium, hyperthyroidism, diabetes, alcohol abuse, cigarette smoking, elevated serum N-terminal pro b-type natriuretic peptide (NT-proBNP), frequent premature atrial contractions, and increased P wave dispersion on ECG.5,6

cardiac monitoring for at least 28 days. (Risk factors for

To learn more, visit AAN.com/guidelines

Level B

PFO is highly prevalent, found in approximately 25% of the general adult population on agitated-saline TEE and cadaveric studies.7,8 Transcranial Doppler ultrasonography (TCD) has been demonstrated shunting, although TCD does not rule out other cardioembolic sources PFO morphology, including anatomic size, location, and length of the tunnel.9 and otherwise cryptogenic stroke, with increasing PFO prevalence in younger patients with stroke and those lacking traditional vascular risk factors such as hypertension, hypercholesterolemia, and diabetes.10-12 The risk of stroke recurrence in patients with PFO and no other etiology

obesity, sleep apnea, enlarged left atrium, elevated NT-proBNP, frequent premature atrial contractions, and increased P wave dispersion. Recently published guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society recommend prolonged ECG monitoring following cryptogenic stroke for patients older than 40 years, although more research is needed to with PFO.14) In patients being considered for PFO closure, clinicians should assess for cardioembolic sources using transthoracic echocardiography (TTE) followed by TEE assessment if the

Level B Studies should use bubble contrast, with and without Valsalva maneuver, to assess for right-to-left shunt and determine degree of shunting.

treated with medication alone. This stroke risk is generally lower than the stroke risk caused by other possible common stroke mechanisms.13 Thus, if an alternative plausible higher risk mechanism of stroke is

©2020 American Academy of Neurology

Read New Practice Advisory on Thymectomy for Myasthenia Gravis continued from cover to be a safe therapeutic option. The practice advisory recommends that clinicians should counsel patients considering a less invasive thymectomy technique that it is uncertain whether the benefit attained by extended transdermal thymectomy will also be attained by less invasive approaches. Minimally invasive approaches commonly used today for thymectomy have not been studied in a rater-blinded, randomized, controlled trial.

Thymectomy, coupled with prednisone, is probably effective at increasing the chance a patient with anti-acetylcholine receptor antibody-positive MG will attain minimal manifestation status (MMS). Patients undergoing thymectomy who attain MMS may be able to reduce the dosage of steroids needed to control MG. Read the guideline and access summaries for clinicians and families/caregivers and a slide presentation set at AAN.com. For more information, email guidelines@aan.com or call (612) 928-6056. 

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Conferences & Community

Congratulations New Fellows of the American Academy of Neurology!

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

Muataz Fairooz Abd, MD, FAAN Fatima Abrantes-Pais, MD, FAAN Jagadish B. Agadi, MD, FAAN Anwar Ahmed, MD, FAAN Jessica Ailani, MD, FAAN Mohamed Hassan Al Zwahmah, MD, MBBS, FAAN Tariq Jawaid Alam, MD, FAAN Talal Muteb Al-Harbi, MD, FAAN Uzma Ali, MD, MBBS, FAAN Renato Anghinah, MD, FAAN Miguel Chuquilin Arista, MD, FAAN Edward Avila, DO, FAAN Madhav H. Bhat, MD, FAAN Danish Bhatti, MD, FAAN Cynthia Bodkin, MD, FAAN Russ A. Bodner, MD, FAAN Leonor Cabral-Lim, MD, FAAN Jonathan Cahill, MD, FAAN Jorge Martinez Cerrato, MD, FAAN Choon H. Cha, MD, FAAN Yoon-Hee Cha, MD, FAAN Jeffrey Chavin, MD, FAAN Nicole C. Clark, MD, FAAN Christopher Coffey, PhD, FAAN Howard Colman, MD, PhD, FAAN Alastair J. Corbett, MD, FAAN Gabriele C. De Luca, MD, PhD, FAAN Daniel DiCapua, MD, FAAN Renaud A. Du Pasquier, MD, FAAN Lorraine L. Edwards, MD, FAAN Emily Rubenstein Engel, MD, FAAN Kevin M. Faber, MD, FAAN Paul Brent Ferguson, MD, FAAN Joseph M. Ferrara, MD, FAAN Johanna Therese Fifi, MD, FAAN Richard S. Finkel, MD, FAAN Dimitry A. Fomin, MD, FAAN Susan Fox, MD, FAAN Gail J. Francis, MD, FAAN Natasha Frost, MD, FAAN Juan Fueyo, MD, FAAN Jong-Ling Fuh, MD, FAAN P.C. Gilvaz, MD, FAAN G. Peter Gliebus, MD, FAAN Amartyadeb Goswami, MD, FAAN Carlos A.M. Guerreiro, MD, FAAN Jeff Guptill, MD, FAAN Matthews W. Gwynn, MD, FAAN Nazar H. Haidri, MD, FAAN Andrea Leigh Haller, MD, FAAN Ihtsham Haq, MD, FAAN Adam L. Hartman, MD, FAAN

Michael Rubin, MD, FAAN Anhar Hassan, MBBCH, FAAN Seward B. Rutkove, MD, FAAN Stuart H. Isaacson, MD, FAAN Nerses Sanossian, MD, FAAN Rosette A. Jabbour, MD, FAAN Ann Scher, PhD, FAAN Mandar S. Jog, MD, FAAN Syndi Seinfeld, DO, FAAN James C. Johnston, MD, JD, FAAN Richard G. Selbst, MD, FAAN Arun Kachroo, MD, FAAN Nilay R. Shah, MD, FAAN Brendan J. Kelley, MD, FAAN Adam Kelly, MD, FAAN Tarannum Khan, MD, MBBS, FAAN Kleopas A. Kleopa, MD, FAAN Jessica B. Kraker, MD, FAAN Ronald E. Kramer, MD, FAAN Rahul Vittnal Kulkarni, MD, FAAN Visit AAN.com/view/FAANReq to see if you’re Doris Kung, DO, FAAN eligible for the FAAN designation—or encourage Roman L. Kutsy, MD, FAAN a qualifying colleague to apply. Applying for Kristina Lafaye, MD, FAAN FAAN status is free, acknowledges exemplary Paul Evans Later, MD, FAAN work and achievements in the neurosciences, Victoria Leavitt, PhD, FAAN the clinical practice of neurology, or academic/ Hongyan Li, MD, PhD, FAAN Bertrand C. Liang, MD, FAAN administrative neurology; helps set you apart Viveca Bhat Livezey, MD, FAAN both within the Academy and throughout your David W. Loring, PhD, FAAN professional career; and offers eligibility to Georgios Manousakis, MD, FAAN serve on the AAN Board of Directors.  Zoltan Mari, MD, FAAN Peter J. McAllister, MD, FAAN Logan McDaneld, MD, FAAN Vicki Shanker, MD, FAAN Jagan Pillai, MD, PhD, FAAN Prafula Shembalkar, MD, FAAN Jeffrey Waugh, MD, PhD, FAAN Joshua M. Shulman, MD, FAAN Maria Kataki, MD, PhD, FAAN Florence Shum, DO, FAAN Mathula Thangarajh, MD, PhD, FAAN Tanya Simuni, MD, FAAN Mitchell Wallin, MD, MPH, FAAN C.J.M. Sindic, MD, FAAN Perry Shieh, MD, PhD, FAAN Divya Singhal, MD, FAAN Stacey Clardy, MD, PhD, FAAN Jeenendra Prakash Singhvi, MD, FAAN Tatsuro Mutoh, MD, PhD, FAAN A. Robert Spitzer, MD, FAAN Kimberly A. Mebust, MD, FAAN Jose I. Suarez, MD, FAAN Jeremy Moeller, MD, FAAN Aimee Szewka, MD, FAAN Susanne Muehlschlegel, MD, MPH, FAAN Esteban Luis Taleti, MD, FAAN Suraj Muley, MD, FAAN Kevin Tan, MD, FAAN Matthew J. Murnane, MD, FAAN Richard M. Trosch, MD, FAAN Najib I. Murr, MD, FAAN Georgios Tsivgoulis, MD, FAAN Yomi A. Ogun, MD, FAAN R. Scott Turner, MD, PhD, FAAN Yong D. Park, MD, FAAN Joon H. Uhm, MD, FRCP(C), FAAN Erik P.J. Pioro, MD, DPhil, FAAN Eric Joseph Uhrik, DO, FAAN Renu Pokharna, MD, FAAN Charles C. Wang, MD, FAAN Gil Dan Rabinovici, MD, FAAN Sandra Weintraub, PhD, FAAN Mohammad A. Rana, MD, FAAN John Michael Whapham, MD, FAAN Wesley D. Reynolds, MD, FAAN Meredith Wicklund, MD, FAAN Samer Mohammed Saeed Ridha, MD, FAAN Heinz Wiendl, MD, FAAN Olga Vanessa Rios, MD, FAAN Mary Alissa Willis, MD, FAAN Mario Rivera, MD, FAAN Christina Wilson, MD, FAAN Maria Sheila G. Rocha, MD, PhD, FAAN John R. Wilson, MD, FAAN Jesus Hernan Rodriguez, MD, FAAN Allan Ding Wu, MD, FAAN Robert P. Rubens, MD, MBA, FAAN Rana K. Zabad, MD, FAAN 

Interested in Elevating Your Membership Status to FAAN?

Conferences & Community

Live Well, Lead Well Graduate Discovers Lasting Power of Community Physician burnout affects at least 50 percent of US practitioners. Neurology is one of several medical specialties that has both the highest rates of burnout and the lowest rates of work-life balance. The AAN’s Live Well, Lead Well programs are designed specifically to empower neurologists to cultivate well-being and resilience in their lives, increase engagement at work, and develop strong, lasting leadership skills in an effort to reduce and prevent burnout and improve well-being. Attendees share the skills and strategies that they learn during the program with their colleagues, creating an ongoing positive effect in their practice communities.

No one exemplifies the vision and purpose of the program like Rebecca Miller-Kuhlmann, MD, a clinical assistant professor of neurology and neurological sciences at Stanford University in Stanford, CA, and 2018 Live Well, Lead Well graduate who is also a member of the AAN’s Live Well, Lead Well Work Group.

Since participating in the program, Miller-Kuhlmann has implemented successful burnout-reduction strategies among residents and fellows within her own institution and has found inspiration and support in a strong—and ever growing— physician community.

“Whenever you do a program, there are excellent workshops and skills learned in the moment. And then there are the takeaways that have the most lasting power. In the case of my experience with Live Well, Lead Well—two years out—the strongest takeaway for me has been the power of physician community,” explained Miller-Kuhlman. “The program taught us many wellness skills at the individual and group level and also, perhaps by design, caused a bond to form between our group rather quickly—and I think even a bit

Miller-Kuhlmann

surprisingly for many of us. We are still in touch and checking in with one another as a group somewhat regularly, which is remarkable for a group that runs the gamut of geographic locations, practice settings, and career stages.”

During her time in the program, Miller-Kuhlmann worked with another fellow at Stanford to co-develop initial programming for neurology trainees to strengthen the residency community at her institution. “Our initial wellness and mentorship program was met with success and significant movement among many wellness metrics for our residents, fellows, and participating attending neurologists,” she said. The success led Miller-Kuhlmann to eventually organize programming at

The program includes community-building nights around activities such as bowling and ceramics.

Miller-Kuhlmann is pictured above in the front row, second from right.

18

AANnews • May 2020

the attending levels based on the published COMPASS trial whereby groups of attending physicians commit to meet once monthly for six months for lunch or dinner and discuss a topic.

Miller-Kuhlmann also learned that many interventions at the individual and group level have the power to evoke change, but that “finding the perfect intervention is not important because there isn't one.” She explained “there are a thousand things that can be done, and each may have the power to reach a certain subset of interested individuals. Although by all metrics and feedback the program was quite successful, the part of the initial trainee program that I found to be the most innovative—placing the residents and fellows into mentorship teams with attendings—didn’t gel due to the time and logistical constraints of any wellness programming for busy trainees.

Caution has to be taken at every point to walk the line of encouraging our residents and fellows to commit some time to wellness because of the intense dividends it pays in the long run, and to somehow simultaneously avoid being one more task on the residents’ endless to do list and thereby a source of EM: 18 BUSMoverwhelm Recruitment rather Ad—Half Page Horizontal> AN than relief.”

Under Miller-Kuhlmann’s guidance, her institution has changed the format of its trainee wellness program each year of its existence, most recently taking the shape of various sessions where the trainees invite a handful of attendings to discuss a topic of the trainees’ choice, covering everything from "applying for your first job" to "work/life balance throughout the career spectrum."

“Each of the shapes we have trialed for our wellness program thus far have kept the strong initial important aim, while strengthening the precious resource that is physician community,” said Miller-Kuhlmann. “And the innovation has also been possible because of the confidence I have from my Live Well, Lead Well training that many interventions work to bolster physician well-being, doing something is most important, there is no one solution.” 

aced in AANnews 5 x 5.25 +0.125 bleed, 4C

STRONGER BUSINESS ADMINISTRATORS MAKE A MORE EFFICIENT PRACTICE Strengthen your BUSINESS ADMINISTRATOR’S knowledge and skills in neurology with special, reduced rate AAN memberships.

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AAN.com/view/careteam.

AANnews • May 2020 19

Policy & Guidelines

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

Neurology in the Time of COVID-19 Member Perspective by Melissa W. Ko, MD, FAAN, CPE, Member of AAN’s BrainPAC Executive Committee and Member Engagement Committee If your life resembles anything like mine during this COVID-19 pandemic, the new every day routines can feel like the same Groundhog Day on repeat, but the news from media outlets and our organizations are fast paced and changing by the hour. At the AAN, our leadership and advocacy staff are fighting tirelessly on our behalf in the midst of so much disruption. I want to bring you the latest on how the Academy is advocating for us while we serve on the front lines for our patients with neurologic conditions.

AAN President James C. Stevens, MD, FAAN, has in recent days written to Vice President Mike Pence, Secretary of Health and Human Services Alex Azar, Speaker of the House Nancy Pelosi (D-CA), Senate Majority Leader Mitch McConnell (R-KY), and numerous private payers about critically important issues that matter to us neurologists during these challenging times.

The landmark COVID-19 Emergency Relief Bill that was signed into law recently contains many provisions that help us continue to care for our patients, practices, and families including: COVID-19: Greater access to personal protective equipment (PPE), ventilators, and medical supplies for federal and state response efforts; insurance coverage for testing; increased payments of 30 percent to hospitals treating patients with COVID-19; and increased support to the National Institutes of Health ($900 million), Centers for Medicare & Medicaid Services

20

AANnews • May 2020

($200 million), public health data surveillance ($500 million), the Center for Disease Control and Preparedness ($4.3 billion), hospital preparedness ($250 million), and vaccines/therapeutics/diagnostics preparedness ($11 billion) Telehealth: $200 million for the Federal Communications Commission to support health care providers to address coronavirus by providing telecommunications services and devices necessary to enable telehealth services Financial Assistance for Practices: $100 billion made available through grants to reimburse health care providers for COVID-19 related expenses and lost revenue, $3.5 billion in grants for immediate assistance to childcare providers including those who support health care workers Increased Provider Funding: Boost of payments to physicians and health care providers by temporarily lifting the Medicare sequester In addition, the AAN has created the COVID-19 Neurology Resource Center packed with everything you need to know, from the latest science to how to launch telemedicine for your practice.

In closing, borrowed from the Quaker tradition, a word to you, my colleagues, as you care for others each day, “I shall pass this way but once; any good that I can do or any kindness I can show to any human being; let me do it now.” Thank you for all that you do for our patients. Stay well and stay safe. 

Education & Research

Resident & Fellow Section of Neurology Seeks Research Articles The Resident & Fellow section of the Neurology ® journal is specifically interested in receiving submissions from the specialties listed below. These topics focus on a range of critical research needs on areas including new technologies, public health and education, obstacles for neurologists, patient cases in child neurology, subspecialties that are emerging in neurology, and evaluation articles.

Future of Neurology and Technology

be researched on these specialties.

Global and Community Health

If you are interested in investigating these areas, the first step is to contact the Resident & Fellow section editor. If you select one of the suggested titles, it will be considered checked out and no longer listed online. During the six-week checkout period, authors are expected to submit a manuscript; otherwise, the title will be reposted for other researchers. 

Opinion and Special Articles Child Neurology Emerging Subspecialties Journal Club The Resident & Fellow “Call for Authors” page at Neurology.org/CallForAuthors lists specific titles for papers that could

Revised Position Statement Addresses Human Participants in Clinical Research The AAN has revised its 1998 position statement on ethical issues in clinical research to provide guidance to its members involved with research in human participants. The revision outlines a principle-based framework for analyzing some of the most important ethical challenges currently facing neuroscientists, and, by doing so, mitigating the risk to human participants involved in clinical research. An article about the revision appeared in the March 16, 2020, online version of Neurology® and in the April 14, 2020, print issue.

This AAN position statement has been endorsed by the American Neurological Association and the Child Neurology Society.

The article outlines the hope that the application of a principlebased ethical framework will facilitate and lend greater consistency and fairness to both those participating in clinical research and those who stand to either benefit or be harmed by the outcome. These principles should be applied to research design, implementation, and analysis.

Since the first position statement in 1998, there have been enormous changes in clinical research (e.g., extensive progress in genetic research, growth of international clinical research) and in research ethics (e.g., National Institutes of Health rulings on the inclusion of under-represented populations in research, the creation of study registries such as ClinicalTrials.gov, the 2017 update to the Common Rule).

The new position statement provides a framework of principles for the ethical analysis of clinical research, and applies that framework to several important historical, current, and potential future ethical issues in clinical research.

This framework consists of seven principles for the ethical planning, review, and analysis of clinical research. These seven principles, originally developed by Ezekiel Emmanuel and widely promulgated by the NIH, are drawn from the foundational documents of research ethics, including the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, and the US Common Rule. They include social value, scientific validity, fair participant selection, favorable risk-benefit ratio, independent review, informed consent, and respect for participants.

The position statement applies the principlebased framework to analyzing 1) historical issues, including IRB review, equitable participant inclusion, cognitive impairment in research participants; 2) current controversies including international clinical research and the replication crisis; and 3) imminent ethical issues in genetic research. 

AANnews • May 2020 21

Education & Research

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Play the latest Neurology Minute episode. neurology MINUTE

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Get a brief daily digest on what you need to know in the field of neurology!

Subscribe to the Neurology Minute™ podcast and program your Siri, Alexa, or Google Assistant.

Get Free, Discounted Access to AAN Education Resources continued from cover

NeuroSAE 2019 Annual Meeting Edition Take this self-assessment exam prior to launching Annual Meeting On Demand to gauge your strengths and areas in need of further study.

Discounted Subscription on Continuum

Continuum® is always here for you, offering up to 20 AMA PRA Category 1 Credits™ of self-assessment CME per issue.

Subscribe or renew to save 15 percent off the regular AAN member rate! Please note that the discounted price is only available for orders received through Wolters Kluwer and only through July 1, 2020. You will receive both Continuum and Continuum® Audio for only $339.15 for a one-year subscription (the 2020 AAN member rate is $399).

Continuum’s 2020 Topics February: Autonomic Disorders April: Cerebrovascular Disease June: Neurology of Systemic Disease August: Sleep Neurology October: Peripheral Nerve and Motor Neuron Disorders December: Neuro-oncology With a subscription you receive six print issues a year, online access to the complete archive of back issues, plus access to Continuum Audio interviews, each of which also provide selfassessment CME. For more information on Continuum selfassessment CME opportunities, visit ContinuumJournal.com.

If you’re not currently a subscriber and curious about Continuum, check out free articles at continpub.com/free to see what you’re missing.

Additional CME Resources for Members NeuroSAE®: Online self-assessment examination in neurology helps assess your strengths and areas for improvement, compares your performance to other neurologists, and offers up to 8 self-assessment CME credits.* NeuroLearn®: Multimedia suite of online education courses can be taken at your own time and pace, address relevant clinical neurology and timely practice topics, and offer up to two CME credits upon successful completion.* Neurology CME: The AAN’s peer-reviewed, premier medical journal offers the most recent advances in the field with up to 1.5 hours of AMA PRA Category 1 Credits per issue—or up to 72 for a full year.

Neurology Podcast: Earn .5 AMA PRA Category 1 Credit when you listen to weekly podcasts from Neurology and answer the accompanying online questions. *Free access is limited to one course per online learning program at a time.

Medical Students, Business Administrators, and Advanced Practice Providers at the lower dues rate not eligible for free access. 

Quick, Convenient eLearning Opportunities Are Complimentary AAN Member Benefit

PODCAST

Now is a great time to remember that AAN members receive free access to a host of online learning opportunities designed around micro-learning, or short and succinct education content.

NeuroBytes Videos These quick and convenient three- to six-minute videos address timely and relevant topics in neurology, along with additional resources for further self-guided exploration. The catalog continues to grow, with over 30 videos currently available.

Latest topics include Telemedicine Coding: Non Face-toFace E/M Guidelines; What Neurologists Should Know About COVID-19; and The Neurologic Exam via Telemedicine. Visit AAN.com/view/NeuroBytes today and log in with your AAN member ID and password to access.

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Neurology ® Podcast Listen to interviews with authors of the most exciting research articles on weekly podcasts from Neurology ®, the official journal of the AAN. To see the full lineup of AAN Online Learning opportunities, visit AAN.com/Learn. 

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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%

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

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

IMPORTANT SAFETY INFORMATION WARNING: Progressive Multifocal Leukoencephalopathy (PML) TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI. Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH® Prescribing Program.

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

Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis Important Safety Information continues on the following pages. Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

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

ALWAYS

APPROXIMATELY

200,000

COMMITTED TO SAFETY

NEW PATIENTS

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

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

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

PATIENTS TREATED

1 IN 4

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

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

Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken Contraindications TYSABRI is contraindicated in patients who have or have had PML TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI TYSABRI TOUCH Prescribing Program Because of the risk of PML, TYSABRI is available only through a restricted distribution program under a REMS called the TOUCH® Prescribing Program Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI, and complete and sign the Patient-Prescriber Enrollment Form Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI The duration of treatment with TYSABRI prior to onset ranged from a few months to several years Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered Important Safety Information continues on the following pages. Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

IMPORTANT SAFETY INFORMATION (cont’d) Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis (cont’d) Patients being administered TYSABRI are at a higher risk of acute retinal necrosis (ARN), a fulminant viral infection of the retina caused by the family of herpes viruses. Patients with eye symptoms such as decreased visual acuity, redness or eye pain should be referred for retinal screening as serious cases of ARN can lead to blindness of one or both eyes Following clinical diagnosis of ARN, consider discontinuation of TYSABRI Hepatotoxicity Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with TYSABRI in the postmarketing setting Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence) Hypersensitivity/Antibody Formation Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1% Reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain If a hypersensitivity reaction occurs, discontinue administration of TYSABRI and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared with patients who did not develop antibodies to TYSABRI in both MS and CD studies Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment Immunosuppression/Infections The immune system effects of TYSABRI may increase the risk for infections In Study MS1, certain types of infections—including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections—occurred more often in TYSABRI-treated patients than in placebotreated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI in Study MS1 In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids In a long-term safety study of patients, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections over the risk observed with use of TYSABRI alone In Studies MS1 and MS2, the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients In Study MS1, the incidence of serious infections was approximately 3% in TYSABRI-treated patients and in placebo-treated patients.

Most patients did not interrupt treatment with TYSABRI during infections Laboratory Test Abnormalities In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient Adverse Reactions The most common adverse reactions reported at an incidence of ≥10% with TYSABRI and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%) The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% placebo), including urinary tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%) Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

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

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

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

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

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

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

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

1.

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

2.

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

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

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

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

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

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

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

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

4.

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

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

5.

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

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

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

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

<1/1,000

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

†

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

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

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

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

Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with TYSABRI. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that antibodies to the JC virus have not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients’ serostatus may change intermittently.

Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. After plasma exchange, wait at least two weeks to test for anti-JCV antibodies to avoid false negative test results caused by the removal of serum antibodies. After infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 halflives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results.

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

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

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

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

JC virus infection of granule cell neurons in the cerebellum (i.e., JC virus granule cell neuronopathy [JCV GCN]) has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML. JCV GCN can cause cerebellar dysfunction (e.g., ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy. For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended. JCV GCN should be managed similarly to PML. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating TYSABRI. It

presents as a clinical decline in the patient’s condition after TYSABRI removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing treatment with TYSABRI for reasons unrelated to PML. In TYSABRI treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to TYSABRI naïve patients [see Adverse Reactions (6.2)].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 2:

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

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

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2

5 <1

9 4

7 3

3 2 1

2 <1 <1

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

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

Table 3:

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

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

TYSABRI n=983 %

Placebo n=431 %

32 10 8 5 2 1

23 8 6 4 <1 <1

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

6 1

4 0

2

<1

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

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

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

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Blood disorders: hemolytic anemia 8.

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

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

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

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

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

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

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

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

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

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

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

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

17.

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

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

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

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

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

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

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

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

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

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

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

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

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

Education & Research

Apply for UCNS Accreditation of Fellowship Programs by June 1 The United Council for Neurologic Subspecialties (UCNS) is accepting accreditation applications for fellowship training programs through June 1, 2020. Applications received by the deadline will be reviewed at the UCNS Accreditation Council meeting in the fall of 2020. Approved programs will be accredited effective December 1, 2020.

Programs that attain accreditation status offer the core content established by the subspecialty and meet the required quality standards established by UCNS. Residents seeking fellowships in UCNS subspecialty areas know that the UCNS training programs offer the training defined by experts in that subspecialty and the programs have the oversight of the

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UCNS Accreditation Council. Fellows graduating from UCNS-accredited training programs meet the training eligibility requirements for certification in their respective UCNS-recognized subspecialty, creating a strong career path for fellow graduates.

UCNS accredits programs in eight neurologic subspecialty areas including Autonomic Disorders, Behavioral Neurology & Neuropsychiatry, Clinical Neuromuscular Pathology, Geriatric Neurology, Headache Medicine, Neurocritical Care, Neuroimaging, and Neuro-oncology. The next application period deadline will be December 1, 2020.

For more information, visit UCNS.org or contact Amanda Carpenter, UCNS Senior Manager Accreditation, at acarpenter@ucns.org or (612) 928-6065. 

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