2021 June AANnews

VOLUME 34 · ISSUE 6 · JUNE 2021

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

REGISTER NOW FOR JULY VIRTUAL SPORTS CONCUSSION CONFERENCE Latest Concussion Science and Education Get the latest science and education in the world of sports concussion, as well as earn up to 7.5 valuable CME and CE credits, when the always popular AAN Sports Concussion Conference returns via a fully virtual format this July 30 through 31. Registration is now open at AAN.com/SCC. Register by July 22 for the best rates!

VIRTUAL CONFERENCE

JULY 30-31, 2021

The Sports Concussion Conference is a leading voice in shaping the sport-related concussion conversation for all clinicians and scientists involved in the prevention, diagnosis, and management of sport-related concussion at the youth, high school, collegiate, and professional levels. Attendees can once again expect to find top experts presenting the latest scientific information and best practices through a variety of programming.

This year, the two-day conference will focus on advances in the science as well as clinical pearls in the management of concussion. Concussion experts will present up-to-date best practices and emerging scientific information. 

AAN Advocating to Preserve Telehealth Flexibilities, Payment Parity Post-pandemic

Order 2021 Annual Meeting On Demand to Retain Access to Content, CME Through March 31, 2022

Access mobile-friendly content—and CME—from the world’s premier neurology meeting while on the go, anytime, anywhere, through March 31, 2022, when you order the 2021 Annual Meeting On Demand through the AAN’s Online Learning Center at AAN.com/AMOD. Continued on page 20

12 Implementing a Planned

Visit Model for Neurology

›

Like many other industries, neurology practices around the country have been forced by the COVID-19 pandemic to dramatically reshape their delivery of care for the vulnerable populations they treat. Telehealth has become an essential method of delivering care for Tomcik most neurologists, which has only been possible due to the policy flexibilities enacted by Congress, along with the broad interpretation of these provisions by the Centers for Medicare & Medicaid

13 Headache Takes Focus in New

Neurology: Clinical Practice Issue

Continued on page 25

19 Health Care Disparity Programming Debuts at 2021 Annual Meeting

›

Not representative of a patient.

INDICATION KESIMPTA 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 Contraindication: KESIMPTA is contraindicated in patients with active hepatitis B virus infection.

WARNINGS AND PRECAUTIONS Infections: An increased risk of infections has been observed with other anti-CD20 B-cell depleting therapies. KESIMPTA has the potential for an increased risk of infections including serious bacterial, fungal, and new or reactivated viral infections; some have been fatal in patients treated with other anti-CD20 antibodies. The overall rate of infections and serious infections in KESIMPTA-treated patients was similar to teriflunomide-treated patients (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until resolved.

Consider the potential increased immunosuppressive effects when initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA. Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

Make KESIMPTA your 1 st choice for RMS POWER In two Phase 3 pivotal clinical trials vs teriflunomide, KESIMPTA demonstrated: • Significant reduction in ARR of up to nearly 60% vs teriflunomide ((P<0.001)1,2* • Profound reduction in mean number of Gd+ T1 lesions per scan of up to 98% ((P<0.001)1† • Superior reduction in mean number of new or enlarging T2 lesions per year of up to 85% ((P<0.001)1† • Significant risk reduction in 3-month CDP of 34% (P (P=0.002) and 6-month CDP of 32% (P=0.01)1,2†

PRECISION • A targeted and precisely delivered B-cell therapy1,3‡ Safety • Favorable safety profile similar to teriflunomide as demonstrated in 2 pivotal trials1

FLEXIBILITY • The first once-monthly (20 mg), SC, B-cell therapy administered at home or anywhere1§II

Learn more at KesimptaHCP.com Study Design: ASCLEPIOS I and II were 2 identical randomized, active-controlled, double-blind Phase 3 studies in patients with RMS, approximately 40% of whom were DMT treatment naïve. Patients were randomized to double-dummy subcutaneous KESIMPTA (20 mg every 4 weeks) or oral teriflunomide (14 mg daily) for up to 30 months. Primary endpoint was ARR. Key MRI endpoints were number of Gd+ T1 lesions, and annualized rate of new or enlarging T2 lesions. A key clinical endpoint was reduction in risk of 3-month CDP. Treatment duration was variable based on end of study criteria. Maximum duration 120 weeks, median duration 85 weeks.

ARR=annualized relapse rate; CDP=confirmed disability progression; DMT=disease-modifying therapy; Gd+=gadolinium-enhancing; MRI=magnetic resonance imaging; RMS=relapsing multiple sclerosis; SC=subcutaneous. *Primary endpoint: relative reduction in adjusted ARR vs teriflunomide of 51% (0.11 vs 0.22) in ASCLEPIOS I and 59% (0.10 vs 0.25) in ASCLEPIOS II. †Key clinical and MRI endpoints: reduction in mean number of Gd+ T1 lesions per scan vs teriflunomide of 98% (0.01 vs 0.45) in ASCLEPIOS I and 94% (0.03 vs 0.51) in ASCLEPIOS II; reductions in T2 lesions vs teriflunomide of 82% (0.72 vs 4.00) in ASCLEPIOS I and 85% (0.64 vs 4.15) in ASCLEPIOS II; reduced risk in 3-month CDP vs teriflunomide of 34% (15.0 vs 10.9) and 6-month CDP of 32% (8.1 vs 12.0) in pooled populations from both trials. ‡ The precise mechanism by which KESIMPTA exerts its therapeutic effects is unknown. § The initial dose period consists of 20 mg SC doses at Weeks 0, 1, and 2.

II KESIMPTA Sensoready® Pens must be refrigerated at 2°C to 8°C (36°F to 46°F). Keep product in the original carton to protect from light until the time of use. Do not freeze. To avoid foaming, do not shake.

References: 1. Kesimpta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 2. Hauser SL, Bar-Or A, Cohen JA, et al; for the ASCLEPIOS I and ASCLEPIOS II trial groups. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546-557.

3. Huck C, Leppert D, Wegert V, et al. Low-dose subcutaneous anti-CD20 treatment depletes disease relevant B cell subsets and attenuates neuroinflammation. J Neuroimmune Pharmacol. 2019;14(4):709-719.

IMPORTANT SAFETY INFORMATION (cont) WARNINGS AND PRECAUTIONS (cont) Hepatitis B Virus: Reactivation: No reports of hepatitis B virus (HBV) reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ofatumumab at higher intravenous doses for chronic lymphocytic leukemia (CLL) than the recommended dose in MS and in patients treated with other anti-CD20 antibodies.

Infection: KESIMPTA is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients treated with ofatumumab at higher intravenous doses for CLL than the recommended dose in MS. Perform HBV screening in all patients before initiation of KESIMPTA. Patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], should consult liver disease experts before starting and during KESIMPTA treatment.

Progressive Multifocal Leukoencephalopathy: No cases of progressive multifocal leukoencephalopathy (PML) have been reported for KESIMPTA in RMS clinical studies; however, PML resulting in death has occurred in patients being treated with ofatumumab at higher intravenous doses for CLL than the recommended dose in MS. In addition, JC virus infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. If PML is suspected, withhold KESIMPTA and perform an appropriate diagnostic evaluation. If PML is confirmed, KESIMPTA should be discontinued.

Vaccinations: Administer all immunizations according to immunization guidelines: for live or live-attenuated vaccines at least 4 weeks and, whenever possible at least 2 weeks prior to starting KESIMPTA for inactivated vaccines. The safety of immunization with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with KESIMPTA During Pregnancy. For infants whose mother was treated with KESIMPTA during pregnancy, assess B-cell counts prior to administration of live or live-attenuated vaccines. If the B-cell count has not recovered in the infant, do not administer the vaccine as having depleted B-cells may pose an increased risk in these infants.

Injection-Related Reactions: Injection-related reactions with systemic symptoms occurred most commonly within 24 hours of the first injection, but were also observed with later injections. There were no life-threatening injection reactions in RMS clinical studies.

The first injection of KESIMPTA should be performed under the guidance of an appropriately trained health care professional.

If injection-related reactions occur, symptomatic treatment is recommended.

Reduction in Immunoglobulins: As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed.

Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections and after discontinuation of therapy until B-cell repletion.

Consider discontinuing KESIMPTA therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Fetal Risk: Based on animal data, KESIMPTA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to KESIMPTA in utero. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving KESIMPTA and for at least 6 months after the last dose.

Most common adverse reactions (>10%) are upper respiratory tract infection, headache, injection-related reactions, and local injectionsite reactions.

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

KESIMPTA, the KESIMPTA logo, and SENSOREADY are registered trademarks of Novartis AG.

Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, New Jersey 07936-1080

© 2020 Novartis

10/ 20

KSM-1395660

KESIMPTA® (ofatumumab) injection, for subcutaneous use Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE KESIMPTA 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.

4 CONTRAINDICATIONS KESIMPTA is contraindicated in patients with: • Active HBV infection [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Infections An increased risk of infections has been observed with other anti-CD20 B-cell depleting therapies.

KESIMPTA has the potential for an increased risk of infections, including serious bacterial, fungal, and new or reactivated viral infections; some of these infections have been fatal in patients treated with other anti-CD20 antibodies. In Study 1 and Study 2 [see Clinical Studies (14) in the full prescribing information], the overall rate of infections and serious infections in patients treated with KESIMPTA was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in the randomized clinical relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until the infection is resolved.

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants When initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1) and Clinical Pharmacology (12.2) in the full prescribing information]. KESIMPTA has not been studied in combination with other MS therapies.

Hepatitis B Virus Reactivation There were no reports of HBV reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (CLL) (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies.

Infection KESIMPTA is contraindicated in patients with active hepatitis B disease.

Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). HBV screening should be performed in all patients before initiation of treatment with KESIMPTA. At a minimum, screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with KESIMPTA. These patients should be monitored and managed following local medical standards to prevent HBV infection or reactivation.

Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.

Although no cases of PML have been reported for KESIMPTA in the RMS clinical studies, PML resulting in death has occurred in patients being treated with ofatumumab for CLL (at substantially higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). In addition, JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold KESIMPTA and perform an appropriate diagnostic evaluation. Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. 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.

If PML is confirmed, treatment with KESIMPTA should be discontinued.

Vaccinations Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines,

and whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines.

KESIMPTA may interfere with the effectiveness of inactivated vaccines.

The safety of immunization with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or liveattenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion [see Clinical Pharmacology (12.2) in the full prescribing information].

Vaccination of Infants Born to Mothers Treated with KESIMPTA During Pregnancy In infants of mothers treated with KESIMPTA during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.

Inactivated vaccines may be administered, as indicated, prior to recovery from B-cell depletion, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.

5.2 Injection-Related Reactions In Study 1 and Study 2, systemic and local injection reactions were reported in 21% and 11% of patients treated with KESIMPTA compared to 15% and 6% of patients treated with teriflunomide who received matching placebo injections, respectively [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information].

Injection-related reactions with systemic symptoms observed in clinical studies occurred most commonly within 24 hours of the first injection, but were also observed with later injections. Symptoms observed included fever, headache, myalgia, chills, and fatigue, and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening injection reactions in RMS clinical studies.

Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching, and pain.

Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in RMS clinical studies. The first injection of KESIMPTA should be performed under the guidance of an appropriately trained healthcare professional. If injection-related reactions occur, symptomatic treatment is recommended.

5.3 Reduction in Immunoglobulins As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 7.7% of patients treated with KESIMPTA compared to 3.1% of patients treated with teriflunomide in RMS clinical trials [see Adverse Reactions (6.1)].

Treatment was discontinued because of decreased immunoglobulins in 3.4% of patients treated with KESIMPTA and in 0.8% of patients treated with teriflunomide. No decline in immunoglobulin G (IgG) was observed at the end of the study. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing KESIMPTA therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

5.4 Fetal Risk Based on animal data, KESIMPTA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to KESIMPTA in utero. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving KESIMPTA and for at least 6 months after the last dose [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail elsewhere in the labeling: • Infections [see Warnings and Precautions (5.1)] • Injection-Related Reactions [see Warnings and Precautions (5.2)] • Reduction in Immunoglobulins [see Warnings and Precautions (5.3)] 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 clinical practice.

Approximately 1500 patients with RMS received KESIMPTA in clinical studies. In Study 1 and Study 2, 1882 patients with RMS were randomized, 946 of whom were treated with KESIMPTA for a median duration of 85 weeks; 33% of patients receiving KESIMPTA were treated for up to 120 weeks [see Clinical Studies (14.1) in the full prescribing information]. The most common adverse reactions occurring in greater than 10% of patients treated

with KESIMPTA and more frequently than in patients treated with teriflunomide were upper respiratory tract infections, injection-related reactions (systemic), headache, and injection-site reactions (local). The most common cause of discontinuation in patients treated with KESIMPTA was low immunoglobulin M (3.3%), defined in trial protocols as IgM at 10% below the lower limit of normal (LLN).

Table 1 summarizes the adverse drug reactions that occurred in Study 1 and Study 2.

Table 1: Adverse Reactions in Patients with RMS with an Incidence of at Least 5% with KESIMPTA and a Greater Incidence Than Teriflunomide (Pooled Study 1 and Study 2) KESIMPTA 20 mg N = 946 % 39

Teriflunomide 14 mg N = 936 % 38

Injection-related reactions (systemic)

21

15

Headache

13

12

Injection-site reactions (local)

11

6

Urinary tract infection

10

8

Back pain

8

6

Blood immunoglobulin M decreased

6

2

Adverse Reactions Upper respiratory tract infectionsa

aIncludes

the following: nasopharyngitis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, rhinitis, viral upper respiratory infection, tonsillitis, acute sinusitis, pharyngotonsillitis, laryngitis, pharyngitis streptococcal, viral rhinitis, sinusitis bacterial, tonsillitis bacterial, viral pharyngitis, viral tonsillitis, chronic sinusitis, nasal herpes, tracheitis.

Injection-Related Reactions and Injection-Site Reactions The incidence of injection-related reactions (systemic) was highest with the first injection (14.4%), decreasing with subsequent injections (4.4% with second, less than 3% with third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Two (0.2%) patients treated with KESIMPTA reported serious injection-related reactions. There were no life-threatening injection-related reactions. Most frequently reported symptoms (2% or greater) included fever, headache, myalgia, chills, and fatigue.

In addition to systemic injection-related reactions, local reactions at the administration site were very common. Local injection-site reactions were all mild to moderate in severity. The most frequently reported symptoms (2% or greater) included erythema, pain, itching, and swelling [see Warnings and Precautions (5.2)].

Laboratory Abnormalities Immunoglobulins In Study 1 and Study 2, a decrease in the mean level of IgM was observed in KESIMPTA-treated patients but was not associated with an increased risk of infections [see Warnings and Precautions (5.3)]. In 14.3% of patients in Study 1 and Study 2, treatment with KESIMPTA resulted in a decrease in a serum IgM that reached a value below 0.34 g/dL. KESIMPTA was associated with a decrease of 4.3% in mean IgG levels after 48 weeks of treatment and an increase of 2.2% after 96 weeks.

6.2 Immunogenicity As with all therapeutic proteins, there is 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 medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ofatumumab products may be misleading.

Treatment induced anti-drug antibodies (ADAs) were detected in 2 of 914 (0.2%) KESIMPTA-treated patients; no patients with treatment enhancing or neutralizing ADAs were identified. There was no impact of positive ADA titers on PK, safety profile or B-cell kinetics in any patient; however, these data are not adequate to assess the impact of ADAs on the safety and efficacy of KESIMPTA. 7 DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies Concomitant usage of KESIMPTA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with KESIMPTA.

When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating KESIMPTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of KESIMPTA in pregnant women. Ofatumumab may cross the placenta and cause fetal B-cell depletion based on findings from animal studies (see Data).

Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following maternal exposure to KESIMPTA have not been studied in clinical trials. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown. Avoid administering live vaccines to neonates and infants exposed to KESIMPTA in utero until B-cell recovery occurs [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) in the full prescribing information].

Following administration of ofatumumab to pregnant monkeys, increased mortality, depletion of B-cell populations, and impaired immune function were observed in the offspring, in the absence of maternal toxicity, at plasma levels substantially higher than that in humans (see Data).

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

Data Animal Data Intravenous administration of ofatumumab (weekly doses of 0, 20, or 100 mg/kg) to pregnant monkeys during the period of organogenesis (gestations days 20 to 50) resulted in no adverse effects on embryofetal development; however, B-cell depletion was observed in fetuses at both doses when assessed on gestation day 100. Plasma exposure (Cave) at the no-effect dose (100 mg/kg) for adverse effects on embryofetal development was greater than 5000 times that in humans at the recommended human maintenance dose of 20 mg. A no-effect dose for effects on B-cells was not identified; plasma exposure (Cave) at the low-effect dose (20 mg/kg) was approximately 780 times that in humans at the recommended human maintenance dose (RHMD) of 20 mg/month.

Intravenous administration of ofatumumab (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg) to pregnant monkeys throughout pregnancy resulted in no adverse effects on the development of the offspring. However, postnatal death, B-cell depletion, and impaired immune function were observed in the offspring at the high dose.

The deaths at the high dose were considered secondary to B-cell depletion.

Plasma exposure (Cave) in dams at the no-effect dose (100/20 mg/kg) for adverse developmental effects was approximately 500 times that in humans at RHMD. A no-effect level for mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose.

8.2 Lactation Risk Summary There are no data on the presence of ofatumumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

Human IgG is excreted in human milk, and the potential for absorption of ofatumumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KESIMPTA and any potential adverse effects on the breastfed infant from KESIMPTA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Females of childbearing potential should use effective contraception while receiving KESIMPTA and for 6 months after the last treatment of KESIMPTA [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) in the full prescribing information].

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

8.5 Geriatric Use Clinical studies of KESIMPTA did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger subjects.

Manufactured by: Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 U.S. License No.: 1244 KESIMPTA and SENSOREADY is a [registered] trademark of Novartis AG. T2020-112

AANnews · June 2021

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

13

Family Crisis Prompts Rogens to Help Others Dealing with Alzheimer’s

20

Celebrating Science at Annual Meeting Press Conference

22

Article Examines Neurology Education Funding

Actor Seth Rogen and filmmaker Lauren Miller Rogen established Hilarity for Charity (HFC), a nonprofit organization that helps families deal with Alzheimer’s disease, after Lauren’s mother was diagnosed with the condition at age 55. Through HFC, they support caregivers, inspire a new generation of Alzheimer’s advocates, fund research, and educate about brain health.

Just prior to the recent Annual Meeting, AAN Science Committee Chair Natalia S. Rost, MD, MPH, FAAN, FAHA, hosted a virtual press conference titled, “A Celebration of Science,” featuring the top science at the meeting.

In an effort to illuminate the shortfall between neurology education and the funds required to support it, the AAN Neurology Department Chairs Work Group recently authored an article in the February 2021 Neurology ® journal on “Funding the Educational Mission.”

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.

News Briefs New Undergraduate Program Launched

Industry Partners Hear from AAN Leadership

The AAN has created a new program to interest undergraduate students in neurology and neuroscience. For the Guest Neurologist program, undergraduate students will be invited to join monthly video calls with a medical student and a neurologist, where they will have the opportunity to ask questions about neurology, medical school, and a career in medicine. Share this information with those who may be interested. To learn more, contact Genevieve Gates at ggates@aan.com.

Over 70 industry partners attended the 2021 virtual Annual Meeting Industry Roundtable event. AAN President James C. Stevens, MD, FAAN, gave a presidential update and President Elect Orly Avitzur, MD, MBA, FAAN, discussed her upcoming presidential platform. Staff also spoke about AAN expectations of the new Biden administration and the potential effect on the neurology community. 

AANnews • June 2021 7

President’s Column

Unique Annual Meeting Underscores Changing Times for AAN As I write this column, the AAN has just held its first-ever virtual Annual Meeting, and what a meeting it was! After having to cancel the 2020 Annual Meeting in Toronto and this year’s event planned for San Francisco, this Annual Meeting was attended by more than 13,000 neurology professionals from around the world, all with a shared love of neurology. This number was nearly double what we had anticipated and ranks among our recent in-person meetings!

In addition to the top-notch educational talks and scientific sessions, my favorite parts of the meeting included a tribute to young researchers in 115 countries across the globe; a film about the life of one of my heroes, neurologist and best-selling author Oliver Sacks; the opportunity to host Past President Jim Stevens in my home in New York and reminisce about the surprising challenges and successes of the past pandemic year, fireside; and the joy in seeing two of my former board colleagues receive presidential recognition of the work they have done as volunteers to this organization over an aggregate of nearly 50 years.

It was also exciting for me to listen to the women who gave plenary talks—19 of them, and the largest number ever—and to the courses and sessions on inclusion, diversity, equity, anti-racism, and social justice. This is not the organization I joined in 1984—which, while not the dystopia of the Orwellian novel by that moniker which depicted contempt for women and deemed them inferior—nevertheless, overwhelmingly male in

its leadership and almost exclusively white.

Over the past 37 years since that time, women have grown to comprise 41 percent of this organization; 33 percent of its committee and subcommittee chairs; and 45 percent of the Board of Directors.

Avitzur Moreover, the AAN will have a female president at its helm for at least the next four years. In fact, for the first time in the 73-year history of the AAN, the entire presidential line (president, vice president, and president elect), which meets weekly to discuss the significant topics at hand, is comprised of women! We have more work to do, especially in including more members who are underrepresented in neurology, work that will continue during my term and beyond.

Individually, we all have unique backstories and experiences that have shaped us and our aspirations. But collectively, as we saw during the Annual Meeting, we share a love for our profession: neurology. And that shared love was never better showcased than in the virtual platform where we could network with each other, exchange tips, and even chat during the most exciting educational and scientific sessions that have ever been delivered.

We have no time to rest on our laurels, though. Work is already underway on the 2022 Annual Meeting which Academy leaders and staff hope to see held face-to-face in Seattle. The overwhelming success of our virtual meeting gives us confidence to consider a hybrid meeting next year

8

AANnews • June 2021

that would include a virtual component as well as live, on-site activities, if the pandemic recovery continues at the pace we are all working towards. Whichever the platform, know that it will be done with the resolute determination to provide to you the most rewarding experience possible.

As I continue to address you in this column over the next 24 months, I look forward to featuring more about you, why you love neurology, and what this organization means to you. You have been sharing your experiences with me for the past 20 years for my columns for Neurology Today ®, and I would like to invite you to continue to do so during my presidential term. 

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

NEURO-OTOLOGY APRIL 2021, VOL 27, NO 2

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AANnews • June 2021 9

Board Spotlight

Meet Your New Board Member: Wayne E. Anderson, DO, FAHS, FAAN Wayne E. Anderson, DO, FAHS, FAAN, is a newly elected member of the AAN Board of Directors. He is a neurologist subspecialty certified in headache and in pain medicine, practicing in San Francisco. After residency at University of California, Davis, Anderson worked in both solo and group practice models, including a hybrid private practice within a hospital-based neurology center. The different practice models have offered a unique understanding of the benefits and challenges of both employed and private practices.

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

Many years ago, the Academy conducted focus groups in various regions, specifically speaking with people who did not appear to be actively engaged with the Academy. It was at that group I first truly understood the role of the Academy and that it was an organization for all of us. With challenges beginning to emerge in the practice of neurology, I was moved to participate to protect and enhance the field of neurology.

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

I wanted to be on the Board of Directors to continue work increasing the public’s awareness of and importance of the field of neurology, to ensure representation of those in private practice, and to ensure representation of the growing number of DO neurologists.

What experiences and viewpoints do you bring to this role?

I hold a viewpoint that the future of neurology is best ensured when all stakeholders truly understand the value of neurology.

This includes not just our colleagues and patients, but also policymakers, caregivers, and most importantly the public in general. This theme underscored my projects in the advocacy and leadership programs. I have experience both inside and outside the Academy. Although primarily a private practice physician, I have worked in several employment models and have experience in the challenges that underlie the different career options facing neurologists. Within the Academy, I have

PODCAST

experienced participation in different facets Anderson of the organization, each with its own goals. I have participated on committees and subcommittees, working with fellow neurologists addressing the complexities of neurologic practice. I have participated in advocacy and leadership programs to advocate for neurology. And I continue to represent neurology on work groups and committees for other organizations such as the American Board of Anesthesiology and American Academy of Ophthalmology.

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

It is nearly impossible to determine a single answer to that question. If we look at just a few of many examples, I think I have an answer. The Academy is not involved in board certification, but when maintenance of certification changed a few years back, the Academy responded with several free MOC options. When reimbursements for our clinicians were threatened last year, the Academy responded by advocating at Capitol Hill, notably with success. With funding threatened for our researchers, the Academy advocated again, with recent increases in NIH funding for neurologic disease. It can be very hard for all of us in our offices, clinics, research labs, and institutions to see the very active roles the Academy has taken to advocate for our profession. Therefore, the AAN benefits the field of neurology most by meeting its mission statement of being indispensable to its members. 

Neurology ® Podcast:

20 Minutes Pack a Punch!

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

10

AANnews • June 2021

Tools & Resources

How the AAN—and You—Can Influence Payer Policy Have you ever wondered how you can impact change or help influence a payer’s medical policy? The AAN works with commercial payers by responding to payer requests seeking comments from our members to help them understand how a service is performed by neurologists. Commercial payers reach out for both procedure and medication coverage policies and look to specialty societies like the AAN to provide their clinical practice expertise. Academy members play a crucial role in helping influence these medical policies.

To help facilitate these requests, the AAN Coding and Payment Policy (COPAY) Subcommittee works closely with payers like UHC, Anthem, and Cigna, among others. COPAY receives draft medical policies, determines which are relevant to neurology, and identifies the appropriate SynapseSM community to provide input on the subject matter input. Member comments and expertise helps the AAN provide payers with the most current information and treatment options for patients. Your expertise and knowledge of new and emerging studies can help influence changes in medical policies!

It is important to note not all procedures, medications, or services are covered by a payer. Generally, this is due to a lack of procedure or medication outcomes, medical evidence, or medical necessity requirements. Responding to payers’ requests for feedback provides them with the most up-to-date information and context on the medical necessity of these procedures to help patients.

What if you have a payer that is not currently covering a service you regularly perform or is important for the care of your patients? Review the current coverage policy and see if there is any new evidence or studies that would support the coverage of the service. Contact AAN payer relations and coverage staff at practice@aan.com and they will connect you with the payer or reach out on your behalf. The AAN works hard to build and maintain positive relationships with payers and is happy to contact them to review new evidence or studies that would help support the coverage of a neurology service. There is no guarantee this will change a coverage policy but getting the information in front of the payer could provide them with helpful information to influence future decisions when a medical policy comes up for review. 

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Videos on a variety of topics in neurology Free with membership at AAN.com/NeuroBytes

Tools & Resources

Implementing a Planned Visit Model for Neurology Using a planned visit model (or pre-visit planning) can improve patient experience and reduce visit burden for the treatment team.

Planned visit models involve the practice acting at three points: 1. Coordinating during the current appointment 2. Using a look back prior to the next appointment 3. Planning ahead for future appointments During the current visit, team members can coordinate and schedule follow-up appointments as well as establish laboratory testing needed before the next appointment before the patient leaves the office. Prior to the next appointment, team members look back to collect necessary information for upcoming appointments, which may include use of a visit prep checklist to identify care gaps and reminding patients of upcoming appointments. Planning ahead can include collaboration with treatment team members or team huddle, use of pre-appointment questionnaires or Patient Reported Outcome Measure (PROM) tools, and hand off to clinicians.

Here's an example of how a practice might implement a planned headache visit: During a monthly huddle, the treatment team reviews complex cases and list of patients who are overdue for a follow-up visit using an automated electronic health record (EHR) report. Complex cases that would benefit from imaging in advance of their next appointment are identified and an EHR flag placed in case the patient has a visit scheduled.

Scheduling staff contact patients overdue for a follow-up visit using a phone script. Staff review steps to a planned health care visit that include identification of potential laboratory needs in advance of upcoming visits. Patients previously flagged for imaging are provided instructions on how to complete this prior to their next scheduled visit.

For patients who require laboratory testing or were previously flagged for imaging, a notation is made in the EHR for pending orders and assignment of diagnosis code by the treatment team.

A pre-visit packet of information is mailed or sent via electronic portal to the patient reminding them of the visit and, if indicated, lab testing and imaging steps are included.

One to three days prior to the planned visit, a call is placed to verify appointment date and time, request PROM, such as the Headache Impact Test (HIT-6) or Migraine Disability Assessment Test (MIDAS), be completed prior to the appointment, and remind patients to complete any needed labs and imaging, if they haven’t done so.

After arriving, the patient is examined by staff who take vitals, confirm medication list, lab and imaging results, and HIT-6 or MIDAS results flagged for clinician review. If the patient has not completed the survey in the patient portal or arrives without their paper survey, the HIT-6 or MIDAS is completed by the patient while waiting for the clinician.

The clinician reviews and confirms current diagnosis codes in the problem list, reviews and annotates goals in response to discussion on survey results and enters exam in the charging section using dot phrases in the EHR which can help populate patient instructions or After Visit Summary.

The After Visit Summary is printed and reviewed. Rooming staff return the patient to the scheduling area where the patient is asked for availability and a follow-up visit scheduled at six or 12 months as appropriate.

For more information, visit AAN.com/PRO. 

Registry Participants Complete 2020 MIPS Submission One of the many benefits of the Axon Registry ® is providing AAN members a solution for submitting Merit-based Incentive Payment System (MIPS) reporting to the Centers for Medicare & Medicaid Services (CMS). The 2020 MIPS submission period ended on March 31, 2021. The MIPS score for performance year 2020 will result in payment adjustment of Medicare reimbursements for 2022.

Payment adjustments will be dependent on the overall performance of clinicians.

During the 2020 MIPS submission period, a total of 90 practices submitted their MIPS reporting through the Axon Registry. Sixty practices performed individual MIPS reporting, 30 practices performed group submission, and four practices submitted both individual and group reporting.

MIPS submission through the Axon Registry offers reporting for three out

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AANnews • June 2021

of the four components of the MIPS program. The fourth component, cost, uses Medicare claims data to calculate performance, which means clinicians and groups do not have to submit any data.

The MIPS final score will be between 0 and 100 points. The estimated average score for practices that submitted all three categories through the Axon Registry for the 2020 submission period was 72.69.

Though the MIPS quality category requires the submission of six quality measures, most submissions included more than six quality measures for benchmark creation. Quality measures with benchmarks have the potential to be worth more than three points.

To enroll or learn more about the Axon Registry, visit AAN.com/axon or contact registry@aan.com. 

Family Crisis Prompts Rogens to Help Others Dealing with Alzheimer’s

Headache Takes Focus in New Neurology: Clinical Practice Issue

Actor Seth Rogen and filmmaker Lauren Miller Rogen are featured on the cover of the June issue of Brain & Life®.

They established Hilarity for Charity (HFC), a nonprofit organization that helps families deal with Alzheimer’s disease, after Lauren’s mother was diagnosed with the condition at age 55. Through HFC, they support caregivers, inspire a new generation of Alzheimer’s advocates, fund research, and educate about brain health.

The June issue of Neurology ® Clinical Practice offers readers a wealth of insightful papers and reports with an emphasis on resources related to migraine and headache among other topics.

In continuing coverage of the pandemic, experts address common fears about the COVID-19 vaccines and examine the increase in migraine attacks and offer ways to reduce the severity and frequency of headaches.

In the Disorders department, readers get an in-depth look at dysautonomia disorders, such as postural orthostatic tachycardia syndrome, including how to get an accurate diagnosis and appropriate treatment.

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

Research studies include “Elective Hospitalizations for Intractable Headache: Outcomes and Response Predictors,” by Jessica Kiarashi, MD, et al.; “Response to Mindfulness-Based Cognitive Therapy Differs Between Chronic and Episodic Migraine,” by Elizabeth Seng, PhD, et al; and “Healthcare Utilization and Costs in Patients with Migraine Who Have Failed Previous Preventive Treatments,” by Lawrence Newman, MD, FAAN, et al.

Examples of case studies in this issue are “Sumatriptan Anaphylaxis: A Headache of an Allergy,” by Adrian Y. S. Lee, MBBS, et al.; and “Index Vein in Headache and Neurologic Deficits with Cerebrospinal Fluid Lymphocytosis,” by Anca Loredana Alungulese, MD, et al.

Published six times a year, Neurology: Clinical Practice is available free to all AAN members online and in print for US members only. Visit Neurology.org/cp for more information.  Volume 11,

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AANnews • June 2021 13

FOR PATIENTS WITH RELAPSING FORMS OF MS

PLAYING WITH FEWER RELAPSES • The efficacy of VUMERITY® (diroximel fumarate) is based upon bioavailability studies in patients with relapsing forms of multiple sclerosis and healthy subjects comparing dimethyl fumarate to VUMERITY1 • In Study 1 and Study 2 pivotal trials, dimethyl fumarate demonstrated a 53% and 44% relative reduction in annualized relapse rate (ARR) vs placebo, respectively (0.172 vs 0.364; P<0.0001), (0.224 vs 0.401; P<0.0001)1

Indication

• Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present

Important Safety Information

Herpes Zoster and Other Serious Opportunistic Infections • Serious cases of herpes zoster have occurred in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY), including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on VUMERITY for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered • Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment • Consider withholding VUMERITY treatment in patients with herpes zoster or other serious infections until the infection has resolved

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

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

WARNINGS AND PRECAUTIONS Anaphylaxis and Angioedema • VUMERITY can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in patients taking dimethyl fumarate (which has the same active metabolite as VUMERITY) have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue VUMERITY and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema Progressive Multifocal Leukoencephalopathy • Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate (which has the same active metabolite as VUMERITY). PML is an opportunistic viral infection of the brain caused by the JC virus ( JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial • PML has occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9 × 10 9/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8×10 9/L persisting for more than 6 months • At the first sign or symptom suggestive of PML, withhold VUMERITY and perform an appropriate diagnostic evaluation.

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

© 2021 Biogen. All rights reserved. 02/21 VUM-US-0458 v3

Lymphopenia • VUMERITY may decrease lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (which has the same active metabolite as VUMERITY), mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable.

Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with dimethyl fumarate or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 10 9/L or ≤0.5 x 10 9/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years) • In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced lymphocyte counts <0.5 x 10 9/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. Neither VUMERITY nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts

Full access to Biogen Support Services • Helping patients start treatment, manage common side effects, and navigate financial assistance

Learn more about additional studies on VUMERITY in RRMS patients2,3

Visit www.vumerityhcp.com

RRMS=relapsing-remitting multiple sclerosis.

• Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with VUMERITY, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of VUMERITY in patients with lymphocyte counts less than 0.5 x 10 9/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if VUMERITY is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution Liver Injury

• Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY) in the postmarketing setting.

The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients • Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials with dimethyl fumarate • Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during treatment as clinically indicated. Discontinue VUMERITY if clinically significant liver injury induced by VUMERITY is suspected Flushing

• VUMERITY may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials of dimethyl fumarate (which has the same active metabolite as VUMERITY), 40% of dimethyl fumarate-treated patients experienced flushing.

Flushing symptoms generally began soon after initiating dimethyl fumarate and usually improved or resolved over time.

In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization

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

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

Study Designs • Study 1: A 2-year, randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. Secondary endpoint: ARR. • Study 2: A 2-year, multicenter, randomized, double-blind, placebo-controlled study in 1417 patients with RRMS. Primary endpoint: ARR. References: 1. VUMERITY Prescribing Information, Biogen, Cambridge, MA. 2. Naismith RT, et al. CNS Drugs. 2020;34(2):185-196. doi:10.1007/ s40263-020-00700-0 3. Naismith RT, et al. Mult Scler. Published online November 4, 2019. doi:10.1177/1352458519881761

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse Reactions (6.2)].

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

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

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

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

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

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

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

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

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

Adverse Reactions

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

Placebo (N=771)%

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

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

Lymphopenia 2 <1 Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during Gastrointestinal treatment, as clinically indicated. Discontinue VUMERITY if clinically Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, significant liver injury induced by VUMERITY is suspected. abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and 5.6 Flushing VUMERITY may cause flushing (e.g., warmth, redness, itching, and/ usually decreased over time in patients treated with dimethyl fumarate or burning sensation). In clinical trials of dimethyl fumarate (which has compared with placebo. Four percent (4%) of patients treated with the same active metabolite as VUMERITY), 40% of dimethyl fumarate- dimethyl fumarate and less than 1% of placebo patients discontinued treated patients experienced flushing. Flushing symptoms generally due to gastrointestinal events. The incidence of serious GI events was began soon after initiating dimethyl fumarate and usually improved 1% in patients treated with dimethyl fumarate. or resolved over time. In the majority of patients who experienced Hepatic Transaminases flushing, it was mild or moderate in severity. Three percent (3%) of An increased incidence of elevations of hepatic transaminases in patients discontinued dimethyl fumarate for flushing and <1% had patients treated with dimethyl fumarate was seen primarily during serious flushing symptoms that were not life-threatening but led the first six months of treatment, and most patients with elevations to hospitalization. had levels <3 times the upper limit of normal (ULN) during controlled Administration of VUMERITY with food may reduce the incidence of trials. Elevations of alanine aminotransferase and aspartate flushing [see Dosage and Administration (2.3)]. Studies with dimethyl aminotransferase to ≥3 times the ULN occurred in a small number of fumarate show that administration of non-enteric coated aspirin (up to patients treated with both dimethyl fumarate and placebo and were a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence balanced between groups. There were no elevations in transaminases or severity of flushing [see Clinical Pharmacology (12.3)]. ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases 6. ADVERSE REACTIONS The following important adverse reactions are described elsewhere were <1% and were similar in patients treated with dimethyl fumarate or placebo. in labeling: • Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions Section (5.2)] • Herpes Zoster and Other Serious Opportunistic Infections [see Warnings and Precautions (5.3)] • Lymphopenia [see Warnings and Precautions (5.4)] • Liver Injury [see Warnings and Precautions (5.5)] • Flushing [see Warnings and Precautions (5.6)]

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

Adverse Reactions in Clinical Studies with VUMERITY

In clinical studies assessing safety in patients with RRMS, approximately 700 patients were treated with VUMERITY and approximately 490 patients received more than 1 year of treatment with VUMERITY. The adverse reaction profile of VUMERITY was consistent 6.1 Clinical Trials Experience with the experience in the placebo-controlled clinical trials with Because clinical trials are conducted under widely varying conditions, dimethyl fumarate. adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval not reflect the rates observed in clinical practice.

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

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

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

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

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

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

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

Inform patients to swallow VUMERITY capsules whole and intact.

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

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

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

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

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

(MMF) or similar to (HES) those in humans at the RHD. Flushing and Gastrointestinal (GI) Reactions 8.2 Lactation Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are Risk Summary There are no data on the presence of diroximel fumarate or metabolites the most common reactions, especially at the initiation of therapy, and (MMF, HES) in human milk. The effects on the breastfed infant and on may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI milk production are unknown.

The developmental and health benefits of breastfeeding should be reactions. Advise patients experiencing flushing that taking VUMERITY considered along with the mother’s clinical need for VUMERITY and with food (avoid high-fat, high-calorie meal or snack) or taking a nonany potential adverse effects on the breastfed infant from the drug or enteric coated aspirin prior to taking VUMERITY may help [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness established.

in

pediatric

patients

have

not

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

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

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

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

Conferences & Community

Health Care Disparity Programming Debuts at 2021 Annual Meeting Inclusion is the reason the AAN was founded. To be an organization that is the home for all neurologists. It is what makes us stronger.

In 2020, the AAN Board of Directors adopted a new goal to be a fully inclusive, deliberately diverse, and anti-racist organization. We also expanded our core values of Diversity and Equity to now include Inclusion, Diversity, Equity, Anti-racism, and Social Justice, otherwise known as IDEAS. We are working hard to achieve this new goal and demonstrate these expanded values through an actionable roadmap approved by the Board. Members should look for these monthly updates in AANnews to follow our progress.

At the virtual 2021 Annual Meeting, the issue of health care disparities was featured as an official scientific and education topic for the first time. This new subject added valuable breadth and depth to the content delivered at the Annual Meeting, including a variety of curricula for attendees to explore. The programs included Experiential Learning Area presentations, education programming, as well as research presentations in a standalone scientific platform session and poster presentations.

The scientific abstract topic was developed by the Science Committee based on the recommendations established by the AAN’s Special Commission on Systemic Racism and Inequalities in Society. Science Committee Chair Natalia S. Rost, MD, MPH, FAAN, FAHA, feels this was an important addition to Annual Meeting Science. “The inclusion of Health Care Disparities as a scientific abstract topic was imperative to increase AAN members’ knowledge and awareness on disparities in neurologic care,” she said. “This will allow the latest, cutting-edge research on this important topic to be a part of the great collection of science presented at the Annual Meeting.”

A highlight of the education programming was the Health Care Equity Symposium, which included the inaugural Cheryl A. Jay Keynote Lecture “Structural Equity: Lessons from 2020” given

by Joseph Betancourt, MD, MPH, the vice president and chief equity and inclusion officer of Massachusetts General Hospital.

This program was viewed live by over 619 attendees, including 20 scholarship recipients.

The scholarship recipients were selected for their desire to learn more about disparities and work toward equity in neurologic care. This year-long scholarship program kicked off at the Annual Meeting with the recipients attending a full day of symposium programming, including a specialized workshop on bias. Over the next year, they will participate in additional workshops aimed to educate in more detail about disparities

Rost

Fullam

Nwankwo

and mitigation strategies. The program is overseen by a physician work group led by AAN members Jeffrey C. McClean II, MD, FAAN, and Morgan Jordan, DO. Scholarship recipients Timothy R. Fullam, MD, and Chinasa Nwankwo, MD, believe this was a beneficial experience. “I am incredibly thankful to the AAN for providing this programming,” said Fullam. “The foundation provided to recognize and approach disparities in our health system, both through the small group work provided by the scholarship as well as the various programming throughout the Annual Meeting, will be an asset to continuing on this career long learning path in order to help make our health system not only more equitable for our patients, but also for each member of our health care teams.”

Said Nwankwo, “As a scholarship recipient, I am looking forward to learning practical ways to enhance inclusion efforts on a national and local level. I was very impressed with the tangible evidence of commitment of the AAN to expand their efforts focused on diversity, equity, and inclusion at the Annual Meeting. The Health Care Equity Symposium was amazing, and you can catch this session on the Annual Meeting On Demand.

You will be sure to be inspired!”

For more about the AAN’s efforts around health care disparities and IDEAS, visit AAN.com/IDEAS. 

AANnews • June 2021 19

Conferences & Community

Celebrating Science at Annual Meeting Press Conference Just prior to the recent Annual Meeting, AAN Science Committee Chair Natalia S. Rost, MD, MPH, FAAN, FAHA, hosted a virtual press conference titled, “A Celebration of Science,” featuring the top science at the meeting.

Thanh N. Nguyen, MD, Boston University School of Medicine, shared the insights from “Global Impact of the COVID-19 Pandemic on Stroke Care and Intravenous Thrombolysis.” The objectives of this research were to measure the global impact of the pandemic on the volumes for intravenous thrombolysis (IVT), IVT transfers, and stroke hospitalizations over four months at the height of the pandemic (March 1 to June 30, 2020) compared with two control four-month periods.

The goal of “Long-term Survival of Participants in the CENTAUR Trial of AMX0035 for ALS” was to report results

of a long-term overall survival analysis of participants in the CENTAUR trial of AMX0035 for ALS, as explained by Sabrina Paganoni, MD, PhD, of Massachusetts General Hospital in Boston.

“Comparison of Neurofilament Light and Total Tau as Bloodbased Biomarkers of Neurodegeneration: Associations with Cognition and Neuroimaging Outcomes,” was discussed

by Michelle M. Mielke, PhD, Mayo Clinic in Rochester, MN. Researchers compared plasma total tau and neurofilament light as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline, and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume.

These abstracts represent some of the breaking science presented at the Annual Meeting that generate AAN media coverage around the world. 

Order 2021 Annual Meeting On Demand to Retain Access to Content, CME Through March 31, 2022 continued from cover Features include: 300+ hours of content, including top sessions like the Hot Topics Plenary Session, Assessment of Rapidly Progressive Dementias, Neuroimaging for the General Neurology: Brain, Oliver Sacks Film, and the Frontiers Plenary Session

Attention Gold Registrants: You Already Have Access!

140+ programs with syllabi

Gold Annual Meeting registrants already have access to Annual Meeting On Demand as part of their registration package. Simply log in at Learning.aan.com and browse to the “Conferences On Demand” tab. 

25+ exclusive bonus presentations Integrated CME testing Ability to earn and claim up to 68 AMA PRA Category 1 Credits™ through March 31, 2022 

20

AANnews • June 2021

AAN Members Champion National Wellness Activities Three AAN members who have been instrumental in the AAN’s Wellness Joint Coordinating Council (WJCC) have taken on additional national leadership roles.

Neil A. Busis, MD, FAAN, is now serving as co-leader of the National Academy of Medicine Clinician Well-being Collaborative COVID-19 Working Group, helping to address the short- and long-term impacts of COVID-19 going into 2022.

“The COVID-19 working group is focused on weaving together piecemeal, immediate responses during COVID-19 to create a systematic set of well-being efforts post- pandemic,” said Busis. The goal is to position decision makers to address the long-term impacts of COVID-19, which include the mental health needs of clinicians and the implications for the national health care workforce. To accomplish this, the working group plans to keep abreast of COVID-specific developments, and coordinate with other Action Collaborative working groups to ensure alignment of activities.”

Jeffrey Dewey, MD, is chair of the Back to Bedside Work and Advisory Group for the Accreditation Council for Graduate Medical Education (ACGME). The grant program funds ACGMEaccredited resident- or fellow-run projects around the country focused on giving residents more meaningful contact with their patients. To date the program has funded two cycles of grants for over 60 projects and developed change management curricula for any trainees wishing to be change leaders at their institutions.

“Examples of some projects include a pediatrics residency in which each resident created and shared their own ‘trading card’ templates with patients to make and trade their own cards—a fun way for residents and children to get to know one another better,” said Dewey. “An internal medicine residency created resources to allow cardiology fellows to do teaching simultaneously with rotating residents and patients at the bedside to allow patients to learn more about their conditions and develop stronger therapeutic relationships with the care team. A physical medicine and rehabilitation residency used funds to provide weekly lunch and shift coverage for junior residents and a patient of their choice to connect on a personal level with their patients.”

Busis

Dewey

Milstein

of the AMA since his first year of medical school, having represented New York State in the Medical Student Section, Resident and Fellow Section, and the Young Physician Section prior to his current role.

Currently, the AMA Physician Health Portal contains a host of valuable wellness promotion and management resources for medical students, physicians-in-training, and practicing physicians, including modules focused on the role a health system can play in promoting well-being among its employees; a webinar series covering a range of topics, including wellbeing in medicine and teaching “Stress First Aid;” courses on physician burnout and wellness offering CME; and quick tips and resources of the week straight from experts.

“The hope was that the WJCC could learn from initiatives already in place as well as make sure that the AAN’s Advocacy Committee could consider these issues when thinking about the main priorities for the committee,” said Milstein.

“Physician wellness has been particularly challenged during the pandemic as well as with long-standing regulatory burdens that neurologists face in their daily practice, and these issues have been in the forefront of the Advocacy Committee’s work.” 

In his role as chair of the AAN Delegation to the American Medical Association (AMA), Mark Milstein, MD, FAAN, serves as an AAN liaison for wellness activities supported by the AMA. “The AMA has been very active in the wellness sphere, and I was honored to join the WJCC to serve as a connector between the AAN Advocacy priorities, the AMA’s wellness initiatives, and the WJCC,” said Milstein, who has been an active member

AANnews • June 2021 21

Education & Research

Article Examines Neurology Education Funding In an effort to illuminate the shortfall between neurology education and the funds required to support it, the AAN Department Chairs Work Group recently authored an article in the March 23, 2021, online Neurology ® journal on “Funding the Educational Mission.”

The authors state, “Although it is selfevident that education in neurology is important and necessary, how to fund the educational mission is a frequent challenge for neurology departments and clinicians. Department chairs often resort to a piecemeal approach, cobbling together funding for educators from various sources, but frequently falling short.”

Greer

The goal of the paper is two-fold: 1) to educate the community as to the nature of the problem, as well as potential solutions or sources of funding; and 2) to lobby for better resources to support neurological education moving forward.

“Educating future generations of neurologists is essential to ensuring great neurological care for our patients worldwide and advancing therapeutics,” said David M. Greer, MD, FAAN, lead author.

The idea for the paper was born out of key discussions during the 2018 and 2019 AAN Department Chair Summits. “As part of the AAN Academic Initiative we have been working on a number of critical issues facing academic departments, sharing collective ideas of ways to address these issues,

and generating recommendations to help academic chairs and business administrators,” said Ralph L. Sacco, MD, MS, FAHA, FAAN, former Academy president who chairs the AAN Academic Neurology Initiative. “This paper grew Sacco after we published our paper on funds flow models for academic departments and addresses a major gap in funding that is vital to our future success to promote the neurology pipeline.”

The paper stresses the need for departments and institutions to be nimble and creative in finding ways to fund the time and effort, reviews various funding sources, describes the multiple different teaching models and formats used by the modern student and educator and their associated costs—some of which are exorbitant—and discusses possible nonfinancial incentives, including pathways to promotion, educational research, and other awards and recognition.

Added Sacco, “We hope to share best practices among academic departments and raise the bar for all departments to become more successful in funding our mission to educate and train the next generation of neurologists.” 

UCNS Certification Approved for Advertising Purposes in Texas The Texas Medical Board recently approved the United Council for Neurologic Subspecialties as a certifying board for the purposes of advertising, similar to that of the American Board of Medical Specialties and the American Osteopathic Association Bureau of Osteopathic Specialists.

The approval allows physicians practicing in Texas who are UCNS-certified in Autonomic Disorders, Behavioral Neurology & Neuropsychiatry, Clinical Neuromuscular Pathology, Geriatric Neurology, Headache Medicine, Interventional Neurology, Neurocritical Care, Neuroimaging, or Neuro-oncology to promote their UCNS certification in their advertising. Approval was granted for a five-year period.

Visit UCNS.org/News to learn more. 

Headache Receives Continuum Treatment The new issue of Continuum: Lifelong Learning in Neurology ® explores the latest insights in addressing headache.

Guest Editor Matthew S. Robbins, MD, FAAN, FAHS, said, “In recent years, our understanding of headache disorders has advanced so rapidly that it has led to novel disease-specific treatments that are tolerable and effective. This issue will help the practicing neurologist understand the numerous treatments available for our patients with migraine and other headache disorders, including long-standing acute and preventive medications; newer treatments such as gepants, ditans, and monoclonal antibodies; neuromodulation devices; procedures such as botulinum toxin injections and nerve blocks; and behavioral therapies.”

Robbins

Topics covered in this issue include: Diagnosing Secondary and Primary Headache Disorders David W. Dodick, MD, FAAN, FAHS Pathophysiology of Migraine Ana Recober, MD Acute Migraine Treatment Jessica Ailani, MD, FAHS, FAAN Preventive Migraine Treatment Rebecca Burch, MD Cluster Headache and Other Trigeminal Autonomic Cephalalgias Stephanie J. Nahas, MD, MSEd, FAHS, FAAN Other Primary Headache Disorders Jonathan H. Smith, MD, FAHS Cranial Neuralgias Carrie Robertson, MD, FAHS Headache in Women Jelena M. Pavlović, MD, PhD Headache in Children and Adolescents Christina Szperka, MD, MSCE, FAHS Clinic-based Procedures for Headache Matthew S. Robbins, MD, FAAN, FAHS

Through June 30, 2021, AAN members pay only $339 per year for a subscription to Continuum® and Continuum® Audio, which is a 15-percent discount on the already low AAN member rate of $399. Subscribe or renew at shop.lww.com/Continuum and take advantage of this rate for up to three years. Make sure to select “Member” under “Price Type” and enter code WMQ074AA at checkout to receive the discount. AAN Junior members who are transitioning to neurologist memberships are eligible to receive a 60-percent discount on the already low member rate for the Continuum and Continuum Audio subscription. 

Continuum LIFELONG LEARNING IN NEUROLOGY®

JUNE 2021

VOL. 27

NO. 3

Headache EDITOR-IN-CHIEF: STEVEN L. LEWIS, MD, FA AN GUEST EDITOR: MATTHEW S. ROBBINS, MD, FA AN, FAHS

Spontaneous Intracranial Hypotension Shuu-Jiun Wang, MD The issue includes a postreading self-assessment and test with the opportunity to earn up to 20 AMA PRA Category 1 Credits™ toward Self-assessment CME. Upcoming topics for 2021 include: August: Neuroinfectious Disease October: Neurocritical Care December: Behavioral Neurology and Psychiatry

CONTINUUMJOURNAL.COM

AANnews • June 2021 23

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.

Top Advocacy Priority Continues to be Cognitive Reimbursement We’ve seen major changes in 2021 with the implementation of a new coding and payment structure for evaluation and management (E/M) services that simplifies documentation requirements and provides a substantial increase in reimbursement for neurologists—estimated at +7 percent. This change is a product of a multi-year AAN advocacy effort that reversed a previous proposal that was projected to be highly detrimental to neurology and other cognitive specialties.

However, the AAN knows the economic impact of COVID-19 continues to affect neurology practices across the country and is continually making sure Congress and the administration implement policies to prioritize patient access to care.

Since 2011, Medicare payments have been subject to a twopercent across-the-board reduction, known as the Medicare sequester. The sequester is required by the Budget Control Act and was originally intended to incentivize policymakers to find alternative ways to save money. Last year, Congress acted twice to temporarily avert this cut to alleviate some of the financial pressures placed on medical practices by the COVID-19 pandemic. The delay was set to expire on March 31, 2021, but President Joe Biden recently signed into law a bill to extend the delay through the end of 2021. This was a result of over 500 AAN members emailing their members of Congress using the AAN Advocacy Action Center, and the AAN’s advocacy along with other physician groups.

With the Medicare sequester scheduled to go into effect on January 1, 2022, the AAN is also anticipating other Medicare policies that could negatively affect reimbursement in 2022 by up to 10 percent, leading to a “Medicare cliff.” Nearly 200 AAN advocates met virtually with their congressional offices in May at the annual Neurology on the Hill, and one of the priority issues was addressing this impending Medicare cliff.

The AAN is urging Congress to act as soon as possible to avoid a substantial negative impact on neurologic patient care. You can follow #AANadvocacy on social media for the latest AAN activity in protecting Medicare reimbursement.

Preserving Telemedicine Gains Steam in Congress On April 29, 50 senators reintroduced key telehealth legislation

24

AANnews • June 2021

known as the Creating Opportunities Now for Necessary and Effective Care Technologies (CONNECT) for Health Act of 2021 (S. 1512/H.R. 2903). The CONNECT for Health Act aims to expand coverage of telehealth services through Medicare, make permanent COVID-19 telehealth flexibilities, improve health outcomes, and make it easier for patients to safely connect with their doctors. A one-page summary of this bill can be found here. The fact that half of the Senate supported this legislation at its outset is a testament to the broad support that telehealth has on Capitol Hill.

In another sign of progress, the Ways and Means Health Subcommittee held a hearing on April 28 focused exclusively on telehealth. Surprisingly, this is the first ever hearing devoted to telehealth within the Ways and Means Committee, which is the oldest standing committee in the House, founded in 1789. The AAN’s recent letter outlining our federal telehealth policy priorities was recognized by Health Subcommittee Chair Rep. Lloyd Doggett (D-TX-35) during his opening remarks.

This is already the second hearing on this issue in the 117th Congress, following one that took place in the House Energy and Commerce Committee in February.

To help build on this momentum, AAN advocates urged Congress to support the CONNECT for Health Act (S. 1512/H.R. 2903), along with the Telehealth Modernization Act (S. 368/H.R. 1332), to help maintain access to telehealth for neurologic patients following the public health emergency.

Congress Debates Measures to Lower Rx Prices Efforts to improve the affordability of prescription drugs were in the spotlight over the last few weeks, as both Democratic and Republican leadership began to release their proposals to lower the costs of prescription drugs in the United States.

House Democrats reintroduced their signature bill, the Elijah E. Cummings Lower Drug Costs Now Act (H.R. 3).

House Republicans reintroduced their signature bill, the Lower Costs, More Cures Act of 2021 (H.R. 19).

The AAN supports lowering the cost and improving access to prescription medications and is working closely with the key congressional champions on this issue as it moves forward. 

AAN Advocating to Preserve Telehealth Flexibilities, Payment Parity Post-pandemic continued from cover Services (CMS). Before the pandemic, Medicare coverage for telehealth services was available only in a remote or rural coverage area, providers needed to be in a clinic or hospital site of service, and a patient had to be at a specific “originating site” such as a physician’s office. These requirements and many other restrictions were lifted due to the COVID-19 public health emergency.

The AAN has been strongly advocating for additional flexibilities to promote access to telehealth services. During the past year, there have been significant advocacy wins including coverage and payment parity for medically necessary telehealth services, including telephone services. In the 2021 Medicare Physician Fee Schedule final rule, CMS implemented several permanent flexibilities that we supported, including additional services being added to the Medicare telehealth list, new coding and payment for an extended virtual check-in service, and modifications to direct supervision requirements.

As COVID-19 vaccination rates increase, the ability for neurologic patients to access telehealth services is threatened by the impending end of the public health emergency. The AAN is advocating for Congress to preserve the progress that has been made in continuity of health care by passing legislation that makes permanent many of the flexibilities, including removing geographic and originating site restrictions

for patients. Permanent telehealth access was one of the main issues discussed by nearly 200 advocates at the recent virtual advocacy event Neurology on the Hill.

Now that telehealth use has accelerated due to the pandemic, the AAN is committed to growing our development and implementation of evidence-based policies and procedures to support telehealth. A new Telehealth Subcommittee was recently formed to support this long-term goal and will focus on developing member resources and expertise on coverage, coding, documentation, and reimbursement policies; quality measures; legal and liability issues; advocacy positions; and optimal workflow and technology infrastructure.

“Neurologists have really been on the leading edge of various types of telehealth for a long time, but the COVID-19 pandemic has highlighted the importance of teleneurology as a means to provide crucial neurological care,” said Telehealth Subcommittee member Colleen B. Tomcik, MD. “The AAN’s newly created Telehealth Subcommittee is an important and timely initiative to inform and engage AAN members, innovate in this rapidly evolving area, and advocate for high-quality, accessible virtual care for people with neurological conditions.”

Learn more at AAN.com/telehealth. 

AANnews • June 2021 25

American Brain Foundation

Congratulations 2021 Next Generation Research Grant Recipients!

In its ongoing mission to bring researchers and donors together in the fight against brain disease, the American Brain Foundation has named its 2021 recipients of the Next Generation Research Grants. Awarded in collaboration with the American Academy of Neurology, these grants fund innovative research of early-career investigators, encourage passion for research, and lay the groundwork for future success.

Congratulations to the following: Jonathan Brent, MD, PhD Northwestern University ALS Funded by The ALS Association and the American Brain Foundation

Helen Hwang, MD, PhD Washington University in St. Louis Parkinson's Disease Funded by the Parkinson’s Foundation and the American Brain Foundation

Paul Sampognaro, MD University of California, San Francisco ALS Funded by The ALS Association and the American Brain Foundation

Matthew Burns, MD, PhD University of Florida Cognitive Aging and Age-related Memory Loss Funded by the McKnight Brain Research Foundation through the American Brain Foundation

Renatta Knox, MD, PhD Nationwide Children’s Hospital Neuromuscular Disease Funded by the Muscle Study Group and the American Brain Foundation

Samuel Terman, MD University of Michigan Epilepsy Funded by the American Epilepsy Society, the Epilepsy Foundation, and the American Brain Foundation

Alexander Gill, MD, PhD Johns Hopkins University Multiple Sclerosis Funded by the National Multiple Sclerosis Society and the American Brain Foundation

Ikjae Lee, MD Columbia University Medical Center ALS and Related Disorders Funded by the CReATe Consortium and the American Brain Foundation

Wai-Ying Wendy Yau, MD Massachusetts General Hospital Cognitive Aging and Age-related Memory Loss Funded by the McKnight Brain Research Foundation through the American Brain Foundation

The American Brain Foundation was founded in 1992 by the American Academy of Neurology to help fund its world-renowned research program. The Foundation is dedicated to the relentless pursuit of better treatments, prevention, and the discovery of cures across the spectrum of brain diseases and disorders. Learn more at AmericanBrainFoundation.org/Researchers. 

Are You Getting Your AANe-news?

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

Or update your email address at AAN.com/MemberProfile.

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26

AANnews • June 2021

2021 NEXT GENERATION RESEARCH GRANTS MEET THE 2021 RESEARCHERS

Jonathan Brent, MD, PhD ALS

Matthew Burns, MD, PhD Cognitive Aging and Age-Related Memory Loss

Alexander Gill, MD, PhD Multiple Sclerosis

Helen Hwang, MD, PhD Parkinson’s Disease

Renatta Knox, MD, PhD Neuromuscular Disease

Ikjae Lee, MD ALS

Paul Sampognaro, MD ALS

Samuel Terman, MD Epilepsy

Wai-Ying Wendy Yau, MD Cognitive Aging and Age-Related Memory Loss

The American Brain Foundation was founded by the American Academy of Neurology (AAN) to bring researchers and donors together to cure brain diseases and disorders. Our Next Generation Research Grants program funds the innovative research of early-career investigators, encouraging a passion for research and laying the groundwork for future success. By partnering with the AAN, we access the best and brightest minds to source the most high-risk and high-reward research.

Learn more about the 2021 class of Next Generation Research Grants recipients at AmericanBrainFoundation.org/Researchers

In patients with relapsing forms of multiple sclerosis (RMS)

START WITH THE POWER AND EXPERIENCE OF TYSABRI

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

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

1,2

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

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

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

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

MORE THAN

APPROXIMATELY

200,000

15 YEARS OF EXPERIENCE

NEW PATIENTS

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

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

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

PATIENTS TREATED

1 IN 3

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

VISIT TimeForTYSABRI.com IMPORTANT SAFETY INFORMATION (cont’d) WARNING: Progressive Multifocal Leukoencephalopathy (PML) (cont’d)  Adverse events that may occur during plasma exchange (PLEX) include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively studied in TYSABRI-treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML  JCV infection of granule cell neurons in the cerebellum, i.e., JCV granule cell neuronopathy (GCN), with symptoms similar to PML, has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML and can cause cerebellar dysfunction. Diagnosis and management of JCV GCN should follow guidance provided for PML  Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI-treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after PLEX was used to eliminate circulating TYSABRI. It presents as a clinical decline in the patient’s condition after TYSABRI removal (and, in some cases, after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing treatment with TYSABRI for reasons unrelated to PML. In TYSABRI-treated patients with PML, IRIS has been reported within days to several weeks after PLEX. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken Contraindications  TYSABRI is contraindicated in patients who have or have had PML  TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI TYSABRI TOUCH Prescribing Program  Because of the risk of PML, TYSABRI is available only through a restricted distribution program under a REMS called the TOUCH® Prescribing Program  Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI, and complete and sign the Patient-Prescriber Enrollment Form Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis  TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses  Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI  The duration of treatment with TYSABRI prior to onset ranged from a few months to several years  Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered  Patients being administered TYSABRI are at a higher risk of acute retinal necrosis (ARN), a fulminant viral infection of the retina caused by the family of herpes viruses. Patients with eye symptoms such as decreased visual acuity, redness or eye pain should be referred for retinal screening as serious cases of ARN can lead to blindness of one or both eyes  Following clinical diagnosis of ARN, consider discontinuation of TYSABRI Important Safety Information continues on the following pages. Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

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

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

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

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

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

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

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

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

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

1.

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

2.

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

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

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

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

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

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

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

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

4.

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

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

5.

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

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

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

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

1/10,000

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

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

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

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

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

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

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

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

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

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

There are no known interventions that can adequately treat PML if it occurs. Three sessions of PLEX over 5 to 8 days were shown to accelerate TYSABRI clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients, alpha-4 integrin receptor binding remained high. Adverse events which may occur during PLEX include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively studied in TYSABRI-treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML. JC virus infection of granule cell neurons in the cerebellum (i.e., JC virus granule cell neuronopathy [JCV GCN]) has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML. JCV GCN can cause cerebellar dysfunction (e.g., ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy. For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended. JCV GCN should be managed similarly to PML. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI treated patients who developed PML and subsequently discontinued TYSABRI. In almost

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 2:

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

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

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2

5 <1

9 4

7 3

3 2 1

2 <1 <1

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

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

Table 3:

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

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

TYSABRI n=983 %

Placebo n=431 %

32 10 8 5 2 1

23 8 6 4 <1 <1

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

6 1

4 0

2

<1

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

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

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

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8.

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

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

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

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

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

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

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

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

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

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

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

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

17.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Vascular Neurologist—University of Illinois, Chicago/ Department of Neurology, Chicago, Illinois The University of Illinois at Chicago (Department of Neurology) and the UI Hospital and Health Sciences System are undergoing a major Neurology expansion. Positions are currently available for Vascular Neurologists. Successful candidates will join a multidisciplinary team that treats a high volume of complex stroke patients as part of UI Health’s Comprehensive Stroke Certified programs. The ideal candidate should have completed an ACGME-approved fellowship and be board certified (or board eligible) in vascular neurology and have a strong academic interest.

A track record of leadership and research is preferred but not required. The new faculty will have access to cutting edge treatment modalities and will have a significant impact on building the programs further. Salary/rank/ tenure is commensurate with experience. A competitive start-up package including protected time for academic development is available to qualified applicants. Interested parties should send curriculum vitae and statement of interest to FD Testai, MD, PhD, c/o David Katz at davkatz@ uic.edu. Please call (312) 355-1748 for additional information.

The University of Illinois at Chicago is an Equal Opportunity, Affirmative Action employer. Minorities, women, veterans and individuals with disabilities are encouraged to apply.

Neuro-oncologist—Cleveland Clinic, Cleveland, Ohio The Cleveland Clinic Brain Tumor & Neuro-Oncology Center within the Neurological Institute is seeking a neuro-oncologist at the assistant/associate or full professor level with strong clinical and clinical research interests in brain tumors.

The candidate should be board certified in neurology or medical oncology with a career focus in neuro-oncology or with neuro-oncology training. The position will have a strong emphasis on clinical and translational research.

The Brain Tumor & Neuro-Oncology Center (BTNC) is a unique multidisciplinary unit within the Cleveland Clinic Neurological Institute and Taussig Cancer Institute. It is a full member of the Adult Brain Tumor Consortium (ABTC), Brain Tumor Trials Collaborative (BTTC) and offers trials through NRG, industry and our own investigator-initiated trials. BTNC is dedicated to clinical excellence, innovative research and academic achievement. The position provides the opportunity for clinical care of brain tumor patients as well involvement in clinical trials development and NCI funded research. This dynamic position commands an extremely competitive salary enhanced by an attractive benefits package including but not limited to: Excellent medical, dental, vision coverage, Comprehensive disability and life insurance benefits, Medical malpractice & tail coverage provided, Generous time away coverage for vacation, sick time, holidays and CME meeting time, Highly competitive retirement plans with employer contribution, Faculty appointment available at the Cleveland Clinic Learner College of Medicine commensurate with experience.

Interested candidates, please include a current CV and cover letter with your application. Contact Nathan Elting eltingn@ccf.org

Center offer comprehensive care to achieve accurate diagnosis of nerve and muscle diseases and rely upon stateof-the-art treatment modalities to optimize quality of life.

We invite highly qualified candidates who are committed to excellence in patient care, possess strong clinical skills and have an interest in clinical investigation and education. The ideal candidate is one with experience in clinical trials and a demonstrated interest in basic or translational research in ALS. An endowed chair and significant funds for program development are available to the qualified candidate. This dynamic position commands an extremely competitive salary enhanced by an attractive benefits package including but not limited to: Excellent medical, dental, vision coverage, Comprehensive disability and life insurance benefits, Medical malpractice & tail coverage provided, Generous time away coverage for vacation, sick time, holidays and CME meeting time, Highly competitive retirement plans with employer contribution, Faculty appointment available at the Cleveland Clinic Learner College of Medicine commensurate with experience. Interested candidates, please include a current CV and cover letter with your application. Contact Nathan Elting eltingn@ccf.org Neuromuscular Neurologist—Cleveland Clinic, Cleveland, Ohio

CME meeting time, Highly competitive retirement plans with employer contribution, Faculty appointment available at the Cleveland Clinic Learner College of Medicine commensurate with experience. Please include a current CV and cover letter with your application. Contact Nathan Elting eltingn@ccf.org 

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Cleveland Clinic’s Neurological Institute is recruiting a full-time Neuromuscular Neurologist. Expertise in the specific area of nerve and muscle diseases is required as well as Board certification/board eligibility in Neurology and Neuromuscular diseases as well as EMG and/or Clinical Neurophysiology. The Neuromuscular Center at Cleveland Clinic specializes in the diagnosis, treatment, and research of these and other neuromuscular disorders. Specialists at the Neuromuscular Center offer comprehensive care to achieve accurate diagnosis of nerve and muscle diseases and rely upon state-of-the-art treatment modalities to optimize quality of life. We invite highly qualified candidates who are committed to excellence in patient care, possess strong clinical skills and have an interest in clinical investigation and education. Candidates with neurological subspecialty interests will also be considered.

This dynamic position commands an extremely competitive salary enhanced by an attractive benefits package including but not limited to: Excellent medical, dental, vision coverage, Comprehensive disability and life insurance benefits, Medical malpractice & tail coverage provided, Generous time away coverage for vacation, sick time, holidays and

ALS Research focused Neuromuscular Neurologist— Cleveland Clinic, Cleveland, Ohio Cleveland Clinic’s Neurological Institute is recruiting a full-time Neuromuscular Neurologist experienced in the care and investigation of patients with ALS and related disorders. Expertise in the specific area of nerve and muscle diseases is required as well as Board certification/board eligibility in Neurology and Neuromuscular Medicine. The Neuromuscular Center at Cleveland Clinic specializes in the diagnosis, treatment, and research of these and other neuromuscular disorders. Specialists at the Neuromuscular

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JUNE 1

Apply for UCNS Fellowship Training Program Accreditation UCNS.org/Accreditation

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Application Deadline: Diversity Leadership Program AAN.com/DLP

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Early Registration Deadline: Sports Concussion Conference AAN.com/SCC

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Sports Concussion Conference AAN.com/SCC

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Application Deadline: Emerging Leaders Program AAN.com/ELP

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Application Deadline: CHP: 21 Advocacy Awareness Ad: AANnews: Half Page Horizontal Practice Leadership Program USAGE: High Resolution PDF to be placed in AANnewse SPECS: TrimAAN.com/PLP Size 8.25"x5.4375", Full Bleed +0.125", 4C

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