2021 July AANnews

VOLUME 34 · ISSUE 7 · JULY 2021

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

ADVANCED PRACTICE PROVIDER NEUROLOGY EDUCATION SERIES RETURNS Registration Opens August 3 Due to the popularity of the inaugural 2020 virtual series, the Advanced Practice Provider Neurology Education Series will return this September 6 through November 22 to offer advanced practice providers (APPs) a convenient, online opportunity to get overviews, updates, and resources on a variety of core topics in clinical neurology and the business of APPs.

AAN Advanced Practice Provider Neurology Education Series 2021 A Virtual Experience

The 2021 series will feature all new content, an increase in CME—up to 12—and will take place over 12 weeks. The series will include completely new content that will cover clinical anatomy/ neuroanatomy. Programming—including six Q&A and networking sessions with speakers throughout the series—is designed by physicians and APPs, for APPs and will be relevant to both APPs as well as students and trainees looking to deepen their understanding of neurology. Registered attendees will receive weekly emails with resources and access to that week’s course.

Visit AAN.com/APP to learn more and register before September 2 to take advantage of discounted rates. 

ABPN Grant Offers Diplomates Complimentary Access to AAN CME Opportunities

Early Registration Savings End July 22 for July Virtual Sports Concussion Conference

The American Board of Psychiatry and Neurology (ABPN) has offered a generous grant to the Academy that will provide all AAN members and ABPN diplomates free access to two popular AAN online CME opportunities. Both are available through the AAN Online Learning Center beginning June 7 until December 31, 2021. To access the programs, AAN members should log in to the Online Learning Center at Learning.AAN.com with their AAN ID or associated email address.

Tuesday, July 22, is the deadline to secure the best rates on your opportunity to get the latest science and education in the world of sports concussion, as well as earn up to 10.25 valuable CME and

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VIRTUAL CONFERENCE

JULY 30-31, 2021

19 Apply by October 1 for 2022

AAN Research Program Grants

23 Comment and Sign-on Letters: The Power of Persuasion

24 Telehealth Position Statement

Calls for Permanent Expansion

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Discover an oral therapy for your patients with relapsing forms of multiple sclerosis (MS)1…

ZEPOSIA—FOCUSED ON WHAT COUNTS ZEPOSIA was studied in the largest number of patients with RMS in 2 pivotal head-to-head trials against an active comparator (N=2659)2,3a:

POWERFUL Efficacy1a

Proven superior in reducing relapses vs Avonexc Proven superior in reducing GdE and T2 lesions vs Avonex

COMPARABLE

Safety Profile vs Avonex in Overall Incidence of Adverse Reactions1-3b Consistently low discontinuation rates vs Avonex Comparable rates of serious infections and malignancies vs Avonex

Study designs: SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) were multicenter, randomized, double-blind, double-dummy, active treatment-controlled studies of daily oral ozanimod 0.46 mg (not approved for maintenance dose) or 0.92 mg vs weekly Avonex (interferon beta-1a), 30-μg intramuscular injection. Primary endpoint: ZEPOSIA reduced ARR vs Avonex by 48% at 1 year (0.18 vs 0.35, respectively) and by 38% at 2 years (0.17 vs 0.28, respectively). Secondary endpoints: ZEPOSIA reduced the number of new or enlarging T2 lesions by 48% at 1 year and by 42% at 2 years and reduced the number of GdE lesions vs Avonex by 63% at 1 year and 53% at 2 years.

9 of 10 patients showed no confirmed 3-month disability progression. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.1-3 b Adverse reactions: Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year was 59.8% and 75.5%, respectively, and at 2 years was 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of at least 2% in patients treated with ZEPOSIA and at least 1% greater than Avonex, respectively, were as follows: upper respiratory infection, 26% (vs 23%); hepatic transaminase elevation, 10% (vs 5%); orthostatic hypotension, 4% (vs 3%); urinary tract infection, 4% (vs 3%); back pain, 4%

a

The FIRST AND ONLY S1P With No First-Dose Observation Required1,4,5d

Full Prescribing Information for ZEPOSIA has NO FIRST-DOSE OBSERVATION required NO genetic testing required NO ophthalmic testing required for most patients6e

(vs 3%); hypertension, 4% (vs 2%); and abdominal pain upper, 2% (vs 1%). Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. Upper respiratory infection includes nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. Hepatic transaminase elevation includes alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminase increased. Hypertension includes hypertension, essential hypertension, and orthostatic hypertension. Overall discontinuation rates for ZEPOSIA vs Avonex at 1 year were 6% and 8%, respectively, and at 2 years were 10% and 15%, respectively. Discontinuation rates due to adverse reactions for ZEPOSIA vs Avonex at 1 year were 2.9% and 3.6%, respectively, and at 2 years were 3.0% and 4.1%, respectively.

Serious infections: The rate of serious infections at 1 year for ZEPOSIA was 1.1% vs 0.7% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.9% for Avonex. Malignancy rates: The rate of malignancies at 1 year for ZEPOSIA was 0.2% vs 0% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.5% for Avonex.1-3

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

IMPORTANT SAFETY INFORMATION

Contraindications: • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization,

or Class III/IV heart failure or have a presence of Mobitz type II second or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, unless the patient has a functioning pacemaker • Patients with severe untreated sleep apnea • Patients taking a monoamine oxidase (MAO) inhibitor

Please see Important Safety Information throughout and Brief Summary of full Prescribing Information.

A relapse was defined as the occurrence of new or worsening neurological symptoms persisting for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.2,3

c

Start at ZEPOSIAhcp.com

Before initiating treatment with ZEPOSIA, all patients require a recent CBC including lymphocyte count (within 6 months or after discontinuation of prior MS therapy), an ECG to check for preexisting conduction abnormalities, a recent liver function test (within 6 months), and consideration of current and prior medications, including vaccinations.1 Patients without a confirmed history of varicella (chickenpox) or without documented VZV vaccination should be tested for antibodies. If VZV or other live attenuated immunizations are required, administer at least 1 month prior to initiation.1 For patients with a history of uveitis or macular edema, an ophthalmic assessment is required.1 An up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA, as a transient decrease in heart rate and atrioventricular conduction delays may occur.1

d

Diabetes mellitus and uveitis increase the risk of macular edema; patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation. A prompt ophthalmic evaluation is recommended if there is any change in vision while taking ZEPOSIA.1

e

ARR=annualized relapse rate; CBC=complete blood count; ECG=electrocardiogram; GdE=gadolinium enhancing; RMS=relapsing multiple sclerosis; S1P=sphingosine-1-phosphate; VZV=varicella-zoster virus.

IMPORTANT SAFETY INFORMATION (CONTINUED) Infections: ZEPOSIA may increase the susceptibility to infections. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator.

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

• Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. No cases of PML were identified in active-controlled MS clinical trials with ZEPOSIA. PML has been reported in patients treated with S1P receptor modulators and other MS therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation. If confirmed, treatment with ZEPOSIA should be discontinued • In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immunemodulating therapies used for treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression.

When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA

Discover an oral therapy for your patients with relapsing forms of multiple sclerosis (MS)1…

ZEPOSIA—FOCUSED ON WHAT COUNTS IMPORTANT SAFETY INFORMATION (CONTINUED)

Start at ZEPOSIAhcp.com

Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • with significant QT prolongation • with arrhythmias requiring treatment with Class 1a or III anti-arrhythmic drugs • with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • with a history of Mobitz type II second-degree or higher AV block, sick-sinus syndrome, or sinoatrial heart block Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated Macular edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued Unintended Additive Immunosuppressive Effects From Prior Immunosuppressive or Immune-Modulating Drugs: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation.

Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended Severe Increase in Disability After Stopping ZEPOSIA: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment so patients should be monitored upon discontinuation Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA Most common Adverse Reactions (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

Please see Important Safety Information throughout and Brief Summary of full Prescribing Information.

References: 1. ZEPOSIA. Prescribing information. Bristol Myers Squibb; 2020. 2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol.

2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X 3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8 4. Gilenya. Prescribing information. Novartis Pharmaceuticals Corporation; 2019. 5. Mayzent. Prescribing information.

Novartis Pharmaceuticals Corporation; 2019. 6. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017;13(6):375-382. doi:10.1038/ nrneurol.2017.33

ZEPOSIA® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company.

All other trademarks are the property of their respective owners. © 2020 Bristol-Myers Squibb Company. All rights reserved. Printed in the USA. 08/20 US-ZEP-19-0074

ZEPOSIA® (ozanimod) capsules, for oral use The following is a Brief Summary; refer to full Prescribing Information for complete product information.

1

• Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2)]

INDICATIONS AND USAGE

ZEPOSIA 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.

2

DOSAGE AND ADMINISTRATION

2.1 Assessments Prior to First Dose of ZEPOSIA Before initiation of treatment with ZEPOSIA, assess the following: Complete Blood Count Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1)].

Cardiac Evaluation Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions (5.2)].

Liver Function Tests Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.3)].

Ophthalmic Assessment In patients with a history of uveitis or macular edema, obtain an evaluation of the fundus, including the macula [see Warnings and Precautions (5.7)].

Current or Prior Medications • If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

• Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating ZEPOSIA; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].

If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. 2.2 Dosing Information Maintenance Dosage After initial titration (see Treatment Initiation), the recommended maintenance dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8.

ZEPOSIA capsules should be swallowed whole and can be administered with or without food.

Treatment Initiation Initiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions (5.2)].

Table 1: Dose Titration Regimen Days 1-4

0.23 mg once daily

Days 5-7

0.46 mg once daily

Day 8 and thereafter

0.92 mg once daily

2.3 Reinitiation of ZEPOSIA After Treatment Interruption If a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment using the titration regimen [see Dosage and Administration (2.2)].

If a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned.

4

CONTRAINDICATIONS

ZEPOSIA is contraindicated in patients who: • In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2)]

• Have severe untreated sleep apnea [see Warnings and Precautions (5.2)] • Are taking a monoamine oxidase (MAO) Inhibitor [see Drug Interactions (7.7)] 5

WARNINGS AND PRECAUTIONS

5.1 Infections Risk of Infections ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature.

Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved.

In Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA was similar to that in patients who received interferon (IFN) beta-1a (35% vs 34% and 1% vs 0.8%, respectively). ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes zoster [see Adverse Reactions (6.1)].

The proportion of patients who experienced lymphocyte counts less than 0.2 x 109/L was 3.3%. These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)].

Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection.

Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

Herpes Viral Infection In Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below).

Cryptococcal Infection Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

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. 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.

PML has been reported in patients treated with S1P receptor modulators and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation.

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

ZEPOSIA® (ozanimod) capsules, for oral use Prior and Concomitant Treatment with Anti-neoplastic, Immunosuppressive, or Immune-modulating Therapies In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. Antineoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.

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

No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment.

If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. 5.2 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

ZEPOSIA was not studied in patients who had: • A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months • New York Heart Association Class III / IV heart failure • Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient’s health • Other pre-existing stable cardiac conditions without clearance from a cardiologist • Severe untreated sleep apnea • A resting heart rate less than 55 beats per minute (bpm) at baseline Reduction in Heart Rate Initiation of ZEPOSIA may result in a transient decrease in heart rate. In Study 1 and Study 2, after the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate of 1.2 bpm occurred at Hour 5 on Day 1, returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2)].

In Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a.

Atrioventricular Conduction Delays Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in Study 1 and Study 2 with dose titration, second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females) • With arrhythmias requiring treatment with Class 1a or Class III anti-arrhythmic drugs

• With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications (4)] 5.3 Liver Injury Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. In Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3 times the ULN within approximately 2-4 weeks.

In clinical trials, ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a.

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

Individuals with an AST or ALT greater than 1.5 times ULN were excluded from Study 1 and Study 2. Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA, caution should be exercised when using ZEPOSIA in patients with a history of significant liver disease.

5.4 Fetal Risk There are no adequate and well-controlled studies in pregnant women.

Based on animal studies, ZEPOSIA may cause fetal harm [see Use in Specific Populations (8.1)]. Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specific Populations (8.1)].

5.5 Increased Blood Pressure In Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately.

Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at the recommended doses.

Because of an increased sensitivity to tyramine, patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA. 5.6 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in patients treated with ZEPOSIA as early as 3 months after treatment initiation. In pooled analyses of Study 1 and Study 2, the decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a (60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)), though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV1 or FVC after drug discontinuation. One patient discontinued ZEPOSIA because of dyspnea. Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated.

ZEPOSIA® (ozanimod) capsules, for oral use 5.7 Macular Edema S1P modulators, including ZEPOSIA, have been associated with an increased risk of macular edema.

In Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a.

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

B:11.125" T:10.875" S:9.875"

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy.

The incidence of macular edema is also increased in MS patients with a history of uveitis. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.

5.8 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued.

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

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

5.11 Immune System Effects After Stopping ZEPOSIA After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)].

Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions (7.1)].

6

ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling: • Infections [see Warnings and Precautions (5.1)] • Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.2)] • Liver Injury [see Warnings and Precautions (5.3)] • Fetal Risk [see Warnings and Precautions (5.4)] • Increased Blood Pressure [see Warnings and Precautions (5.5)] • Respiratory Effects [see Warnings and Precautions (5.6)] • Macular Edema [see Warnings and Precautions (5.7)] • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8)] • Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.9)] • Severe Increase in Disability After Stopping ZEPOSIA [see Warnings and Precautions (5.10)] • Immune System Effects After Stopping ZEPOSIA [see Warnings and Precautions (5.11)]

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 clinical practice.

The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies in which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14)].

Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

Table 2: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than IFN beta-1aa (Pooled Study 1 and Study 2)

Adverse Reactions

Studies 1 and 2 ZEPOSIA IFN beta-1a 0.92 mg 30 mcg (n=882) Intramuscularly % Once Weekly (n=885) %

Upper respiratory infectionb

26

23

Hepatic transaminase elevationc

10

5

Orthostatic hypotension

4

3

Urinary tract infection

4

3

Back pain

4

3

Hypertensiond

4

2

Abdominal pain upper

2

1

a

Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. c Includes the following terms: alanine aminotransferase increased, gammaglutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminases increased. d Includes hypertension, essential hypertension, and orthostatic hypertension.

Reduction in Heart Rate Initiation of ZEPOSIA may result in transient decrease in heart rate [see Warnings and Precautions (5.2)].

Respiratory Effects Dose-dependent reductions in absolute FEV1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.6)].

Malignancies Malignancies, such as melanoma, basal cell carcinoma, breast cancer, and seminoma, were reported with ZEPOSIA in the active-controlled trials for ZEPOSIA. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator.

Hypersensitivity Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials.

7

DRUG INTERACTIONS

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

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

ZEPOSIA® (ozanimod) capsules, for oral use Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with ZEPOSIA after alemtuzumab is not recommended.

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

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

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

Because of the potential additive effects on heart rate, treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties [see Warnings and Precautions (5.2)]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought.

7.3 Vaccination During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions (5.1)].

7.4 Strong CYP2C8 Inhibitors Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may increase the risk of ZEPOSIA adverse reactions. Therefore, co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended.

7.5 Breast Cancer Resistance Protein (BCRP) Inhibitors Co-administration of ZEPOSIA with BCRP inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may increase the risk of ZEPOSIA adverse reactions. Therefore, co-administration of ZEPOSIA with inhibitors of BCRP (e.g., cyclosporine, eltrombopag) is not recommended.

7.6 Strong CYP2C8 Inducers Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may decrease the efficacy of ZEPOSIA. Therefore, co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided.

7.7 Monoamine Oxidase (MAO) Inhibitors Co-administration of ZEPOSIA with MAO-B inhibitors may decrease exposure of the active metabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO [see Clinical Pharmacology (12.3)]. The potential for a clinical interaction with MAO inhibitors has not been studied; however, the increased risk of nonselective MAO inhibition may lead to a hypertensive crisis. Therefore, co-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiation of treatment with MAO inhibitors.

7.8 Adrenergic and Serotonergic Drugs Because an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis.

Therefore, co-administration of ZEPOSIA with drugs or over-the-counter medications that can increase norepinephrine or serotonin [e.g., opioid drugs, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclics, tyramine] is not recommended.

Monitor patients for hypertension with concomitant use.

Opioid Drugs Serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration.

Serotonergic Drugs Although a small number of patients treated with ZEPOSIA were concomitantly exposed to serotonergic medications, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration.

Sympathomimetic Medications Concomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects on blood pressure [see Clinical Pharmacology (12.3)]. However, hypertensive crisis has occurred with administration of ZEPOSIA alone [see Warnings and Precautions (5.5)] and hypertensive crisis has been reported with co-administration of other selective and nonselective MAO inhibitors (e.g., rasagiline) with sympathomimetic medications.

7.9 Tyramine MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (tyramine reaction).

Patients should be advised to avoid foods containing a large amount of tyramine while taking recommended doses of ZEPOSIA [see Warnings and Precautions (5.5)].

8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women. In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposures (see Data). The receptor affected by ozanimod (sphingosine-1-phosphate) has been demonstrated to have an important role in embryogenesis, including vascular and neural development.

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 Oral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in a marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. At the no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development, plasma ozanimod exposure (AUC) for ozanimod was approximately 60 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted in a marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations (malformed blood vessels) and skeletal variations at the mid and high doses.

Maternal toxicity was not observed. At the no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal development in rabbit, plasma ozanimod exposure (AUC) was approximately 2 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and lactation resulted in persistent body weight reductions and long-term effects on reproductive (prolonged estrus cycle) and neurobehavioral (increased motor activity) function in offspring at the highest dose tested, which was not associated with maternal toxicity. At the no-effect dose (0.7 mg/kg/day) for adverse effects on pre- and postnatal development, plasma ozanimod exposure (AUC) was 30 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

Following oral administration of ozanimod, ozanimod and/or metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma.

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

ZEPOSIA® (ozanimod) capsules, for oral use 8.3 Females and Males of Reproductive Potential Contraception Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use in Specific Populations (8.1)]. Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown [see Clinical Pharmacology (12.3)].

Use of ZEPOSIA in patients with hepatic impairment is not recommended.

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested.

Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors. At the highest dose tested (2 mg/kg/day), plasma exposure (AUC) for ozanimod was approximately 100 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Mutagenesis Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Metabolite CC1122273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays.

Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay.

Impairment of Fertility Oral administration of ozanimod (0, 0.2, 2, or 30 mg/kg/day) to male and female rats prior to and during mating and continuing through gestation day 7 resulted in no adverse effects on fertility. At the highest dose tested (30 mg/kg/day), plasma ozanimod exposure (AUC) was approximately 1600 times that in humans at the maximum recommended human dose (MRHD) (0.92 mg/day); plasma AUCs for metabolites, CC112273 and CC1084037, at 30 mg/kg/day were 13 and 3 times, respectively, those in humans at the MRHD. 17

PATIENT COUNSELING INFORMATION

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

Risk of Infections Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking ZEPOSIA and for 3 months after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection [see Warnings and Precautions (5.1)].

Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. If immunizations are planned, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. Cardiac Effects Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that to reduce this effect, dose titration is required. Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.2)].

Liver Injury Inform patients that ZEPOSIA may increase liver enzymes. Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine [see Warnings and Precautions (5.3)].

Pregnancy and Fetal Risk Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant [see Warnings and Precautions (5.4)].

Respiratory Effects Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea [see Warnings and Precautions (5.6)].

Macular Edema Advise patients that ZEPOSIA may cause macular edema, and that they should contact their healthcare provider if they experience any changes in their vision. Inform patient with diabetes mellitus or a history of uveitis that their risk of macular edema maybe increased [see Warnings and Precautions (5.7)].

Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provide any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological consequences [see Warnings and Precautions (5.8)].

Severe Increase in Disability After Stopping ZEPOSIA Inform patients that severe increase in disability has been reported after discontinuation of a S1P receptor modulator like ZEPOSIA. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of ZEPOSIA [see Warnings and Precautions (5.10)].

Immune System Effects After Stopping ZEPOSIA Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose [see Warnings and Precautions (5.11)].

Manufactured for: Celgene Corporation Summit, NJ 07901 Patent: www.celgene.com/therapies ZEPOSIA® is a trademark of Celgene, a Bristol-Myers Squibb Company. © 2020 Bristol-Myers Squibb Company. All rights reserved.

ZEP_HCP_BSv.001.05 03/2020

AANnews July 2021

July 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.

17

Trainees: It’s Time to Renew Your Membership for the 2021–2022

22

Neurologists Press Congress on Telehealth, Research Funding, and Medicare Access

27

Quinlan Honored with Ted M. Burns Humanism in Neurology

By renewing your valuable AAN memberships, you can ensure continued connection to your community and access to essential training resources, education, and support to enhance professional development.

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

Due to COVID-19 precautions, the 2021 Neurology on the Hill was a virtual event on May 19, connecting 185 AAN members with the congressional offices of 46 states.

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

John G. Quinlan, MD, has been named the recipient of the American Brain Foundation’s second annual Ted M. Burns Humanism in Neurology Award.

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 World Brain Day 2021 The AAN is participating in World Brain Day 2021 on July 22 in partnership with the World Federation of Neurology.

This year, World Brain Day is dedicated to multiple sclerosis, which affects 2.8 million people worldwide. For patient resources and more on MS, visit brainandlife.org/MultipleSclerosis.

Media Coverage The AAN’s new position statement calling for permanent telehealth expansion following the pandemic was covered by Medscape and Healio, among other outlets. And a Neurology® study suggesting eating a Mediterranean diet may prevent Alzheimer’s disease received

coverage in more than 350 outlets around the world, including Parade magazine, Today.com, and CNN.

E/M Surveys AAN coding advisors and staff are leading the AAN’s participation in AMA Relative Value Scale Update Committee (RUC) surveys to ensure appropriate valuation of E/M services utilized by neurologists. The next phase of revisions to the E/M guidelines and code set was passed by the AMA CPT Editorial Panel and will be effective in 2023.

This includes changes to inpatient and observation care services, consultations, and prolonged services. 

President’s Column

As US Restrictions Ease, India Enduring COVID Horrors As I sit down to write this column in early June, the US continues to experience fewer COVID-19 infections and hospitalizations, 52 percent of Americans have had at least one COVID-19 vaccine, and 42 percent have been fully vaccinated. The CDC has loosened its recommendations for vaccinees, and our organization is beginning to plan for future in-person meetings.

India has been far less fortunate. When the outbreak ebbed this past winter, safety measures were relaxed, and India began to return to pre-pandemic activities such as recreational events, political rallies, and religious festivals. Now, it is experiencing its second surge of COVID-19, one much worse than its first, and its medical community has been almost entirely deployed to care for the nation’s growing number of hospitalized patients.

More than 1,300 doctors have died of COVID since the pandemic started, including 646 since the second wave started in March.

There were 414,188 new cases on May 6—a record high at that point—and almost 4,000 deaths a day. Only 14 percent of its population has been vaccinated, 244 million people, and only three percent are fully vaccinated.

The American Academy of Neurology has over 900 members living in India, second in number to Canada among our international members. There are also about 1,000 Indian American neurologists working as our colleagues in the US, according to Sanjay P. Singh, MD, FAAN, FANA, chair of neurology at Creighton University School of Medicine. When I first started reading about India as part of a story in our pandemic series for Neurology Today ®, I learned from half a dozen of our members who live and work in various parts of India that the nation is comprised of complex and decentralized health systems, and many of its inhabitants suffer from multidimensional deprivation.

About 28 percent of its population of 1.37 billion lived in poverty— before the pandemic struck. Magnified by gaping disparities by caste, class, and gender in access to health care, a premature reopening after its first surge, a vaccine rollout which has yet to fully vaccinate 97 percent of its inhabitants, and new variants which help the virus evade the immune defenses, India is in crisis.

In effort to address the tremendous strain on medical facilities, health care professionals, and the health care infrastructure, the Association of Indian Neurologists in America (AINA) launched an online fundraiser on April 30; all funds raised go to Sewa International, a humanitarian, nonprofit service organization registered in the US. It has focused on the country’s most urgent need—medical supplies—and has procured over 5,000 oxygen concentrators, 250 ventilators, and over 20,000 pulse oximeters

and distributed over 4,000 kits of medicines to health care personnel. To date, the AINA has raised and released $31,800, more than half of its goal of $50,000 through donations.

Avitzur

“More than half of India’s neurologists are functioning like general practitioners taking care of COVID patients, day and night, without breaks, in personal protective equipment, changing their masks, and going right back in, over and over again,” said Dr. Singh, who says how proud he is of the efforts of Indian neurologists and all physicians there. A veteran of three successful missions between 2016 and 2019 to deliver on-site medical care to rural India and train local physicians alongside a medical group of specialists from Omaha, NE, Dr. Singh and his colleagues are now exploring continuing their volunteer work through telemedicine. They are working with the state governments in India again, this time to deliver remote care to small hospitals which lack specialists such as neurologists.

US neurologists have ties to many other nations around the world, and as the COVID-19 pandemic showed, our fates are intertwined.

We have learned a great deal from each other as we struggled to combat the virus and understand its neurologic sequelae and will continue to develop our knowledge of science, epidemiology, and public health from lessons shared with one another. “This crisis makes clear the need for global solidarity and sharing of resources to prevent new infections and provide essential medical treatment to affected individuals,” said Jerome H. Chin, MD, PhD, MPH, FAAN, chair of the AAN International Subcommittee. “As we witness the positive gains in the US and other high-income countries against the spread of the virus, our optimism is tempered by the worsening situation in other parts of the world.” 

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

Those who wish to donate funds for medical care in India may do so by contacting the AINA at 4aina.com. If you are registered to practice neurology in India and would like to help provide telehealth care, you may contact Dr. Singh by email at SanjaySingh@creighton.edu.

To connect with colleagues across the globe, join the SynapseSM Online Community for international members at AAN.com/Synapse.

AANnews • July 2021 11

Board Spotlight

Meet Your New Board Member: Larry B. Goldstein, MD, FAHA, FAAN Larry B. Goldstein, MD, FAHA, FAAN, is the Ruth L. Works Professor and chair, department of neurology; co-director of the Kentucky Neuroscience Institute; co-director of the UK Neuroscience Research Priority Area; and interim director of the UK-Norton Healthcare Stroke Care Network at the University of Kentucky. Goldstein focuses his clinical, research, educational, and service activities on stroke and related disorders. He received the G. Milton Shy Award from the AAN in 1979.

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

I first became involved in the AAN as a medical student member as a way of meeting neurologists from across the country. As my career and experience developed, I found working on committees as a great way of learning from a group of passionate and engaged volunteers and to support our patients and our profession. Over the years, I have been a member of the AAN Quality Standards Subcommittee, the Practice Committee, the Stroke Systems Work Group, the Education Committee, the Joint Audit Committee (vice chair), the Health Policy Subcommittee, the Neurology Chairs’ Work Group, and as an AAN Media Expert with a focus on cerebrovascular disease. I also had been a member of the Continuum® editorial board (editor for practice) and am a member of the Neurology ® editorial board.

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

Our profession as a whole, and academic neurology in particular, face a daunting set of challenges. One of my major motivations in becoming a department chair was to help

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build a program, advance the careers of Goldstein both faculty and trainees, and address wider gaps and disparities in clinical care and care delivery. As a member of the Board, I will have the opportunity to use my experience and perspectives to make a positive difference on a national if not international level.

What experiences and viewpoints do you bring to this role?

My experience in basic translational, clinical, and health services research combined with roles in leading professional guideline writing groups, governmental advocacy, health policy—and now my perspectives leading a department and organizing a university-level research program—combine to give me a unique skill set to advance the missions of the AAN. In your view, how does the AAN benefit the field of neurology most?

The AAN is a wonderful resource for neurologists at every stage of their career and for addressing the needs of patients with neurologic disorders. 

Neurology ® Podcast:

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AANnews • July 2021

Conferences & Community

Join the New Experimental Neurotherapeutics Section in Synapse

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RY/ M

ARCH

disparities and inequities; clinical trial design and implementation; and drug development.

Join the new Experimental Neurotherapeutics Section today at AAN.com/sections. 

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The AAN’s new Experimental Neurotherapeutics Section has been established in SynapseSM to serve the needs and interests of neurologists and other clinical neuroscientists who are interested in developing, evaluating, and implementing new treatments for neurologic diseases. This growing and important subspecialty of neurotherapeutics brings together neurologists in academia, private practice, government, and industry to work with basic neuroscientists, pharmacists, pharmacologists, neurogeneticists, physical therapists, clinical trial coordinators, nurses and nurse practitioners, physician assistants, and statisticians on the development and assessment of Eve b ody has gre ry novel treatments, their subsequent memoriat es, b u t I kn regulatory approval, and their effective somethew very un ing was practice.

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Conferences & Community

Early Registration Savings End July 22 for July Virtual Sports Concussion Conference continued from cover CEU credits, when the always popular AAN Sports Concussion Conference returns via a fully virtual format this July 30 through 31. Visit AAN.com/SCC today!

Once again, the Sports Concussion Conference will serve as 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 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. As a result, participants should be able to describe emerging concepts regarding the pathophysiology of concussion and diagnostic biomarkers; institute clinically useful diagnostic tests when indicated; provide state-of-the-art management of concussed athletes and individuals, including those with persistent symptoms; implement safe and appropriate return to play, school, work, and life decisions; and educate athletes, non-healthcare professionals, and other health care practitioners on key issues related to concussion.

Registration includes participation in the live conference and access to posters, plus session recordings and ability to claim CME through August 31, 2021. For extended access to watch session recordings, purchase the Gold Registration to view session recordings and claim CME through June 30, 2022.

Programming for both days includes the following, all in Eastern Time.

Friday, July 30— Evolving Science of Concussion Updates from the NCAA-DoD CARE Consortium 12:00 p.m.–12:30 p.m.

Clinical Updates Thomas McAllister, MD 12:30 p.m.–1:00 p.m.

Advanced Research Core Updates Michael McCrea, PhD, ABPP 1:00 p.m.–1:15 p.m.

Moderated Q&A Moderator: Brian Hainline, MD, FAAN What Matters: Concussion and Repetitive Head Impact Exposure 1:15 p.m.–1:45 p.m.

Traumatic Encephalopathy and Repetitive Head Impact Exposure Robert Stern, PhD 1:45 p.m.–2:15 p.m.

The Science of Repetitive Head Impact Exposure Stefan Duma 2:15 p.m.–2:30 p.m.

Moderated Q&A Moderator: David Dodick, MD, FAAN 2:30 p.m.–3:15 p.m.

BREAK/Networking Sessions 3:15 p.m.–3:40 p.m.

Computerized Neuro-cognitive Assessments: What Counts Jennifer Wethe, PhD

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3:40 p.m.–4:00 p.m.

Challenges and Opportunities: Concussion Surveillance, Definitions, and Coding Alexiz Peterson, PhD/CDC

12:00 p.m.–12:20 p.m.

Moderated Q&A Moderator: Vernon Williams, MD, FAAN

4:00 p.m.–4:30 p.m.

An Assessment of Emerging Technologies and Biomarkers Nicole Reams, MD, and Meeryo Choe, MD, FAAN

12:30 p.m.–1:05 p.m Post-concussion Sleep Disturbance Phyllis Zee, MD, PhD

4:30 p.m.–5:00 p.m.

Final Q&A Moderators: David Dodick, MD, FAAN, and Brian Hainline, MD, FAAN 5:00 p.m.– 6:00 p.m.

Evening Entertainment: Trivia

Saturday, July 31, 2021— Update with Clinical Pearls 10:00 a.m.–10:30 a.m.

Office (Live and Virtual) Evaluation of Concussion Shaetu Datta, MD, and Teena Shetty, MD 10:30 a.m.–11:00 a.m.

Mental Health Issues After Concussion Kimberly Harmon, MD 11:00 a.m.–11:30 a.m.

Post-traumatic Headache Messoud Ashina, MD, PhD 11:30 a.m.–12:00 p.m.

Post-concussion Dizziness Daniel Gold, DO

12:20 p.m.–12:35 p.m.

BREAK

1:05 p.m.–1:35 p.m.

Post-concussion Exercise John Leddy, MD, FACSM, FACP, and Robert Scales, PhD 1:35 p.m.–2:05 p.m.

Guided Poster Tour 2:05 p.m.–2:55 p.m.

The Most Impactful Advances in Concussion Research: The Year in Review Christina Master, MD, FAAP, CAQSM, and Christopher Giza, MD, FAAN 2:55 p.m.–3:10 p.m.

Moderated Q&A Moderator: Brian Hainline, MD, FAAN 3:10 p.m.–3:15 p.m.

Closing Remarks Brian Hainline, MD, FAAN, and David Dodick, MD, FAAN 

VIRTUAL CONFERENCE

JULY 30-31, 2021

AANnews • July 2021

#NeurologyProud and proud to call the AAN my home.

Share why you are #NeurologyProud on social media.

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Conferences & Community

Trainee Trivia Contest Draws Hundreds In July 2020, the AAN launched a monthly, fun-filled, online case-based neurology trivia contest specifically for neurology trainees. The AAN Trainee Trivia contest took off like a rocket drawing more than 550 participants in its inaugural event, and its popularity continues, averaging 300-400 participants each month.

The lively social event pairs hosts Sashank Prasad, MD, of Harvard Medical School, and Raymond Price, MD, FAAN, of the University of Pennsylvania in challenging attendees’ clinical acumen using compelling cases presented through brief vignettes that incorporate video and photo media. Participants

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AANnews • July 2021

can create and join teams and the winning team earns that session’s title of Top AAN Trainee Trivia Team.

Interested trainees are encouraged to look for access links on the AAN Trainee Trivia page at AAN.com/traineetrivia and AAN Residents and Fellows Facebook group. All residents, fellows, and students are encouraged to take part. The next dates are Tuesday, July 27, and Tuesday, August 31, both from 7:30 p.m. to 8:30 p.m. CT. To learn more, contact Allison Perales at aperales@aan.com. 

Trainees: It’s Time to Renew Your Membership for the 2021–2022 Academic Year Neurology trainees are an important part of our worldwide neurology community and staying connected to colleagues now is more important than ever. By renewing your valuable AAN memberships for the 2021–2022 academic year*, you can ensure continued connection to your community and access to essential training resources, education, and support to enhance professional development, including: Free access to Continuum® and Continuum® Audio Career guidance with job seeker tools including CV support, salary calculator, articles and webinars, and career coaching The latest scientific research and news affecting the neuroscience community Resources including online education and clinical practice guidelines Access to a network of 36,000+ neurologists and neuroscience professionals worldwide Contact your program coordinator if your program typically renews your membership or visit AAN.com/dues to renew. If you have recently completed training, contact AAN Member Services at memberservices@aan.com or (800) 879-1960 (US) or (612) 928-6000 (International) prior to renewing to learn about special early career membership rates. * S tudent, Intern, and Junior memberships run on an academic year (July 1 through June 30), regardless of join date. 

HEADACHE JUNE 2021, VOL 27, NO 3

In Unprecedented Times, Rely on Continuum Join your colleagues who depend on Continuum® and Continuum® Audio to stay informed on the latest in patient care.

AAN members get both for only $399!

ContinuumJournal.com

Education & Research

ABPN Grant Offers Diplomates Complimentary Access to AAN CME Opportunities continued from cover 2020 AAN Fall Conference On Demand Fall Conference On Demand is the comprehensive digital library of content with more than 20 hours of presentations from the virtual 2020 AAN Fall Conference and offers up to 21.5 CME credits. This program offers timely clinical updates from noteworthy experts on the hottest topics in neurology, including a keynote address on COVID-19, real-world issues in practice management, and innovative science.

NeuroSAE 14th Edition The latest edition of the AAN’s popular online selfassessment exam with opportunities to earn eight self-assessment CME credits.

For questions, contact eLearning @aan.com. 

UCNS Continuous Certification Reading Lists and Quizzes Now Available The United Council for Neurologic Subspecialties Continuous Certification (C-cert) reading lists and quizzes are now available at UCNS.org/ReadingLists for diplomates in all UCNS subspecialties. Diplomates who have paid their 2021 C-cert admin fees will receive links to access the quizzes via email.

2021 marks the second year of C-cert, a program in which diplomates maintain their certification by meeting annual requirements as opposed to the previous time-limited certificates and high-stakes recertification examination process. C-cert activities provide subspecialty learning and knowledge assessment to ensure that diplomates are staying up-to-date on the latest science, treatments, and therapeutics relating to their subspecialty, and include reading the annual subspecialty reading list of journal articles and taking and passing a 25-question online post-reading quiz to assess knowledge gained from the journal article content.

For questions, contact Bryan Hagerla, C-cert Manager, at bhagerla@ucns.org. 

Apply by October 1 for 2022 AAN Research Program Grants The American Academy of Neurology is committed to supporting researchers because we know that when you make a profound difference in the lives of researchers you ultimately make a profound difference in the lives of patients with brain disease. The 2022 AAN Research Program grants exemplify this commitment to promoting neurology and neuroscience research training across a wide range of career levels and discovery stages, and we encourage you to visit AAN.com/ResearchProgram to learn more about the following opportunities, the new application process, and to apply by the October 1, 2021, deadline.

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OCTOBE

Career Development Award Funded by the American Academy of Neurology Clinical Research Training Scholarship Funded by the American Academy of Neurology Neuroscience Research Training Scholarship Funded by the American Academy of Neurology Practice Research Training Scholarship Funded by the American Academy of Neurology Clinical Research Training Scholarship in ALS Funded by The ALS Association and American Brain Foundation In collaboration with the American Academy of Neurology Richard Olney Clinician Scientist Development Award in ALS Funded by The ALS Association and American Brain Foundation In collaboration with the American Academy of Neurology Robert Katzman, MD, Clinical Research Training Scholarship in Alzheimer's and Dementia Research Funded by the Alzheimer's Association and American Brain Foundation In collaboration with the American Academy of Neurology Clinical Research Training Scholarship in Lewy Body Diseases Funded by The Mary E. Groff Charitable Trust, the Alzheimer's Association, and American Brain Foundation In collaboration with the American Academy of Neurology Clinical Research Training Scholarship in FTD Funded by the Holloway Family Fund of The Association for Frontotemporal Degeneration and American Brain Foundation In collaboration with the American Academy of Neurology Clinical Research Training Scholarship in Muscular Dystrophy Funded by the Muscular Dystrophy Association and American Brain Foundation In collaboration with the American Academy of Neurology Clinical Research Training Scholarship in Parkinson's Disease Funded by the Parkinson's Foundation and American Brain Foundation In collaboration with the American Academy of Neurology

Clinical Research Training Scholarship in Migraine Funded by Amgen, Inc., and American Brain Foundation In collaboration with the American Academy of Neurology Clinician Scientist Development Award in Myasthenia Gravis Funded by the Myasthenia Gravis Foundation of America and American Brain Foundation In collaboration with the American Academy of Neurology McKnight Clinical Translational Research Scholarship in Cognitive Aging and Age-related Memory Loss Funded by the McKnight Brain Research Foundation through the American Brain Foundation, and the American Academy of Neurology Susan S. Spencer, MD Clinical Research Training Scholarship in Epilepsy Funded by the American Epilepsy Society, Epilepsy Foundation, and American Brain Foundation In collaboration with the American Academy of Neurology 

American Brain Foundation's 2022 Cure One, Cure Many Award In partnership with the Alzheimer’s Association, The Michael J. Fox Foundation for Parkinson’s Research, and the American Academy of Neurology, the American Brain Foundation's 2022 Cure One, Cure Many Award is a new $3 million research award created to improve the diagnosis of Lewy body dementia (LBD), the second most common cause of neurodegenerative dementia after Alzheimer's disease.

Pre-proposals due July 30, 2021.

Learn more at AAN.com/COCM. 

AANnews • July 2021 19

Tools & Resources

Axon 13 Updates: Treatment Prescribed for Acute Migraine Attack The AAN Headache Quality Measurement Set underwent an update and published in Neurology ® in September 2020. With this update, there were changes made to Axon measure 13 that are being implemented in Axon Registry ® for the 2021 reporting year.

These updates have expanded the ways in which a clinician can meet the measure.

Numerator: Patients who were prescribed a guideline-recommended or FDA approved/cleared treatment for acute migraine attacks once during the measurement period.

In addition to prescribing a guidelinerecommended medication or treatment to meet the numerator, the new numerator statement now allows non-guideline-recommended treatments to be provided if they are approved for use in migraine patients by the FDA. Clinicians can also prescribe other treatments such as neuromodulation to meet the numerator.

Denominator: Patients > six years of age diagnosed with migraine.

The new denominator statement expands the measure to children as young as six years old.

Exclusions: All guideline-recommended or FDA approved/cleared treatments are medically contraindicated or ineffective for the patient Patient is already on an effective over-the-counter (OTC) medication or an acute migraine medication prescribed by another clinician

Patient has a history of acute migraine medication overuse and additional medications contraindicated at time of visit Patient has minimal or no pain with migraine Patient and/or caregiver decline The first exclusion listed above was better defined so that a patient needs to have contraindications to all guidelinerecommended or FDA approved treatments rather than just one. The exclusion for OTC medications changed to better specify the difference between OTC and an NSAID that could be prescribed. Lastly, an additional exclusion was added for patients with medication overuse headache.

There are changes to the keywords to reflect the new measure components. Some examples for practices to consider implementing are listed below: Keywords examples to meet the numerator: Imitrex 25mg* gammaCore prescribed Non-invasive vagus nerve stimulator prescribed * Note that there are many medications that can meet the numerator.

Medication names will only be searched in the medication field in the EMR, and not in the free form encounter documentation.

Keyword examples that satisfy the exclusions: All guideline-recommended or FDA approved/cleared treatments are medically contraindicated Patient has history of acute migraine medication overuse Patient is currently taking effective medication You can find more keywords on AAN.com/Axon or by contacting AAN staff at registry@aan.com or your Axon Registry account manager for current Axon Registry users. 

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AANnews • July 2021

AAN Takes Stand Against Neck Restraints In May 2021, the AAN Board of Directors approved the following new position statement on the use of neck restraints in law enforcement.

AAN Position Statement on the Use of Neck Restraints in Law Enforcement Neurology and neuroscientist professionals have a responsibility to work toward improving the health of all members of society and educating the public on how to prevent neurologic injury. The deaths of George Floyd, Eric Garner, and other instances where neck restraints were used by law enforcement have called into question whether these restraints are controllable, safe, and nonlethal.1 In an editorial in JAMA Neurology, the authors review carotid artery physiology and the neurological sequelae that result from restricting blood flow or oxygen to the brain—conditions that occur with the neck restraints commonly used by law enforcement.1 The two neck restraint techniques used by law enforcement are chokeholds (“a physical maneuver that restricts an individual’s ability to breathe for the purposes of incapacitation,” by using pressure on the trachea to restrict oxygen to the brain) and “vascular neck restraints” or strangleholds (“a technique that can be used to incapacitate individuals by restricting the flow of blood to their brain” by using pressure to the carotid arteries).2 The medical literature and the cumulative experience of neurologists clearly indicate that restricting cerebral blood flow or oxygen delivery, even briefly, can cause permanent injury to the brain, including stroke, cognitive impairment, and even death. Unconsciousness resulting from such maneuvers is a manifestation of catastrophic global brain dysfunction. In addition, individuals with underlying cardiovascular risk factors are more vulnerable to suffering significant neurological injury from neck restraint techniques, and the burden of cardiovascular disease in the United States, particularly in communities of color, remains high.3 In sum, the neurological sequelae that result from limiting blood flow or oxygen to the brain due to the use of neck restraints are potentially irreversible and entirely preventable.

Because of the inherently dangerous nature of these techniques, the AAN strongly encourages federal, state,

and local law enforcement and policymakers in all jurisdictions to classify neck restraints, at a minimum, as a form of deadly force. Furthermore, because there is no amount of training or method of application of neck restraints that can mitigate the risk of death or permanent profound neurologic damage with this maneuver, the AAN recommends prohibiting the use of neck restraints.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with 36,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease, and epilepsy. 

References: 1. Berkman, J.M., et al. (2020). "Carotid Physiology and Neck Restraints in Law Enforcement: Why Neurologists Need to Make Their Voices Heard." JAMA Neurol.

2. National Consensus Policy and Discussion Paper on Use of Force [online]. Available at: https://www.theiacp.org/sites/ default/files/2020-07/National_Consensus_Policy_On_Use_Of_ Force%2007102020%20v3.pdf. Accessed April 9, 2021.

3. Carnethon, M.R., et al. (2017). "Cardiovascular Health in African Americans" Circulation (2017); 136:e393-e423.

AANe-news.

Because Your Time Is Valuable.

Sent to your email address the second and fourth Wednesday of each month, AANe-news™ delivers the latest top headlines and resources from the Academy so you can quickly scan and connect directly with the information you need to know.

Another members-only solution from your AAN.

AANnews • July 2021 21

Policy & Guidelines

Neurologists Press Congress on Telehealth, Research Funding, and Medicare Access Due to COVID-19 precautions, the 2021 Neurology on the Hill was a virtual event on May 19, connecting 185 AAN members with the congressional offices of 46 states.

Members urged representatives and senators to take action on three specific “asks” from the AAN: the permanent expansion of telehealth access following the end of the pandemic public emergency; research relief and recovery funding to the NIH and other scientific agencies to mitigate the adverse financial impact of the pandemic on scientific research, including neurologic disorders; and to avert the upcoming “Medicare cliff” that will adversely affect reimbursements and cause a substantial negative impact on patient access to care. 

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AANnews • July 2021

Comment and Sign-on Letters: The Power of Persuasion In addition to meetings and other communications, the AAN formally communicates with members of Congress and federal agencies by writing letters on key issues affecting neurology. Such letters are important to the federal government, as they provide a formal record of support or opposition on a topic, as well as details on how policies affect different populations.

When the Academy submits a letter on its own initiative, it’s referred to as a “comment letter.” When a letter originates as a collaborative effort between other medical specialty societies, patient advocacy groups, etc., it’s called a “sign-on letter.” So far in 2021, the Academy has sent nine comment letters and endorsed 34 sign-on letters on matters that affect members and their patients.

Either way, such letters are written and/or reviewed by AAN physician experts and staff, and the AAN president also reviews if it is a new policy. These letters can also be endorsements of specific bills being introduced in Congress.

The COVID-19 pandemic prompted many letters related to a host of health care matters, from telehealth issues to emergency medical supply concerns. In 2020, the Academy authored 10 letters to policy makers outlining neurology’s specific needs during the public health emergency and joined more than 35 sign-on letters related to COVID-19.

A recent example of a comment letter, where the AAN sent statements to a congressional committee holding a hearing on telehealth, can be read at https://bit.ly/3opIupM.

AAN’s reputation of authority with key legislative and regulatory decision makers. Our comment letters have been cited often over the past several years by such influential publications such as Politico and STAT, helping solidify the AAN’s reputation when staff schedule meetings with these decision makers. 

Collaborative Advocacy Strengthens Neurology Co-signing letters is not the AAN’s only collaborative advocacy work with coalitions of neurologic patient groups and other medical specialty societies. Here are some examples: The AAN convenes a quarterly meeting with neurologic patient groups including the ALS Association, Epilepsy Foundation, Michael J. Fox Foundation, National MS Society, Muscular Dystrophy Association, and others to coordinate advocacy efforts.

Another recent sign-on letter (https://bit.ly/2S25IpE) demonstrates how the AAN joined a letter with several other major medical groups to congressional leadership urging to extend the delay of the Medicare sequester through the end of 2021. Medicare sequestration would result in two-percent across-the-board reduction in Medicare payments. As a result of the advocacy efforts of the medical specialty community, the bill to delay sequestration was signed into law in April 2021.

The Regulatory Relief Coalition is a group of national physician specialty organizations, including the AAN, advocating for regulatory burden reduction in Medicare so that physicians can spend more time treating patients.

These letters also encompass our comments to federal agencies on proposed rules. Once legislation passes Congress, federal agencies must implement the law. Proposed rules are official documents that explains the agency’s plan for implementation and must be published in the Federal Register to notify the public and to give them an opportunity to submit comments. The AAN submits comments on a wide variety of proposed rules, most notably the annual Medicare Physician Fee Schedule proposed rule, which determines reimbursement rates for services under Medicare.

The Academy is a founding member of the American Brain Coalition, which represents professional neurologic, psychological, and psychiatric associations and patient organizations. 

The AAN participates in the Graduate Medical Education Advocacy Coalition, convened by the American Association of Medical Colleges.

While these letters provide the Academy’s viewpoint, they are also effective in building the

AANnews • July 2021 23

Policy & Guidelines

Telehealth Position Statement Calls for Permanent Expansion The AAN published its Telehealth Position Statement in the May 13, 2021, Neurology ® online issue. It updates the 2014 position statement which called for an expansion of telehealth but now also includes what health care providers have learned during the COVID-19 pandemic.

The paper was published just prior to the virtual visit of AAN member neurologists with senators and representatives for the 19th annual Neurology on the Hill. Neurologists asked lawmakers to cosponsor the Telehealth Modernization Act (S. 368/H.R. 1332) or the CONNECT for Health Act (S. 1512/H.R. 2903) to maintain access to telehealth for people with neurologic conditions.

reshaping the delivery of care for their patients. The American Academy of Neurology is asking members of Congress for a Hatcher-Martin permanent expansion of telehealth services to improve safety and access to care and to reduce health care costs for people with neurologic disease.”

During the pandemic, telehealth services have been necessary to minimize the chances of exposure to the highly infectious and deadly virus. For some people with neurologic conditions, telehealth care was needed prior to the pandemic and will continue to be needed long after the quarantines are over.

That is why neurologists are asking that the recent temporary expansion of telehealth services be made permanent.

The AAN Telehealth Position Statement lists not only benefits that include improved access to expert neurologic care, but also enhanced comfort, convenience, and safety particularly for people with limited mobility due to their medical condition or need for home medical support equipment, and reduced travel time and associated costs. Other benefits include decreased time away from work and reduced stress.

“People with neurologic conditions like Alzheimer’s disease, migraine, multiple sclerosis, Parkinson’s disease, ALS, or epilepsy often must visit their neurologist many times a year to monitor the progression of disease and to have medications adjusted,” said Academy President Orly Avitzur, MD, MBA, FAAN. “However, this can be challenging due to mobility ESC: 21 Sports Concusion Conference Ad—Half Page Horizontal> AN lack of reliable transportation, and cost. The COVID-19 Placed issues, in AANnews pandemic has4C led to neurology practices dramatically 8.25 x 5.25 +0.125 bleed,

“Telehealth won’t replace all in-person neurologic care, but for people with neurologic conditions, it has been shown to complement it,” said position statement author Jaime HatcherMartin, MD, PhD, of SOC Telemed in Reston, Virginia. “It is also important that people have options. In addition to video visits, telehealth visits by phone are essential to ensure access to care for people who either cannot afford or who do not have access to high-speed broadband internet.” 

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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.

FDA APPROVES ADUCANUMAB FOR ALZHEIMER’S DISEASE Latest Advocacy News On May 19, 185 members from 46 states participated in the AAN’s first ever virtual Neurology on the Hill, meeting with a total of 246 congressional offices.

Members advocated for AAN priority issues, including the permanent expansion of telehealth access, funding for neurologic research recovery, and averting the upcoming “Medicare cliff” that will adversely affect reimbursements and cause a substantial negative impact on patient access to care. On social media, participants contributed over 1,300 tweets and nearly 900 retweets, totaling over 2 million impressions. Be sure to listen to last Thursday’s Neurology Minute podcast to learn about this year’s priority issues and the experience of Alejandro Vargas, MD. As Congress continues to debate legislation to address infrastructure, the AAN joined 229 members of the Ad Hoc Group for Medical Research to send a letter to Congress urging to include investments in medical research in the final bill.

The AAN also joined nearly 60 members of the GME Advocacy Coalition to send a letter to Congress and the administration expressing support for including additional Medicare-supported GME positions in the bill.

On May 28, President Biden released his full proposed budget for Fiscal Year 2022, which includes a 23-percent increase for the Department of Health and Human Services. The president’s budget is one of the first steps in a lengthy appropriations process that is ultimately

determined by Congress before the start of the new fiscal year on October 1. Learn more details about the AAN’s federal funding priorities. The proposed budget includes:

$52 billion in funding for the National Institutes of Health The creation of a new agency called the Advanced Research Projects Agency for Health (ARPA-H)

Issue in Focus The FDA announced the approval of Alzheimer's drug aducanumab (Aduhelm). The drug was approved under the Accelerated Approval pathway, one of the alternative drug approval pathways detailed in a recent AAN policy brief.

The AAN is reviewing the details of the FDA decision and will provide more details about the indication and labeling to members in the coming days. The AAN formed a work group of experts in health policy, science, and education in July 2020 to prepare for a potential release of aducanumab and its implications for neurologists and their patients. The group prepared recommendations for education and practice resources that the AAN can develop in the coming months to support members with treatment guidance, patient safety, practice workflow, coverage, and reimbursement. Our goal is to provide members with resources and education to know who should be receiving the drug, when to prescribe the drug, how to treat any side effects, and tools to help patients and families. While the AAN did not weigh in on whether the drug should be approved, we did submit comments last October for the FDA to consider around labeling. 

AANnews • July 2021 25

LAUNCH A LIFELONG RESEARCH CAREER

OPENING JULY 1: NEXT GENERATION RESEARCH GRANTS APPLICATIONS Are you a clinician-scientist looking to kickstart your research career in disease areas including ALS, Lewy body dementia, epilepsy, cognitive aging, Parkinson’s, Alzheimer’s, migraine, and more? Then don’t miss your opportunity to apply for a 2022 Next Generation Research Grant.

86%

of our researchers have gone on to secure funding from the NIH and other national funders.

And you could be one of them. The American Brain Foundation’s Next Generation Research Grants fund a broad range of innovative research projects by early-career investigators, encouraging passion for research and laying the groundwork for long-term research careers. Grants are open to applicants who are no more than five to seven years post-residency or PhD. Applications for the 2022 grant program open July 1, 2021.

Learn more and apply at AmericanBrainFoundation.org/For-Researchers Questions? Email grants@americanbrainfoundation.org for more information.

American Brain Foundation

Quinlan Honored with Ted M. Burns Humanism in Neurology Award John G. Quinlan, MD, director of the neuromuscular division in the department of neurology and rehabilitative medicine at the University of Cincinnati College of Medicine, has been named the recipient of the American Brain Foundation’s second annual Ted M. Burns Humanism in Neurology Award. The award recognizes the influence of the most benevolent and innovative professionals in the field of neurology, celebrates neurologists whose work embodies humanism, and inspires neurologists to improve health care delivery and the lives of their colleagues and patients.

In nominating Quinlan for the award, his colleague at the University of Cincinnati, Brett Kissela, MD, MS, FAHA, FAAN, wrote, "Dr. Quinlan has had a spectacular career as a physician, researcher, and educator at the University of Cincinnati College of Medicine. Dr. Quinlan is one of those rare individuals who has accomplished a tremendous amount in all domains of teaching, patient care, and research. Over the past 33 years, he has been an outstanding neurologist, exceptional scholar, and an educational leader within the neuromuscular field, as well as a leader in general within the University of Cincinnati College of Medicine and Medical Center. Dr. Quinlan’s charismatic and selfeffacing style has made him a perennial favorite of students. His numerous recognitions point to his exceptional qualities, not only as a teacher, but also as a wonderful human being who inspires students, colleagues, and patients with his knowledge, integrity, down-to-earth style, and self-deprecating humor."

PublicPolicy: 21 NCP Ad—Half Page Horizontal> AN Placed in Echoing AANnewsKissela’s sentiments, American Brain Foundation Director Jane Ransom said, "Dr. Quinlan is a perfect 8.25 x 5.25Executive +0.125 bleed, 4C

Quinlan example of the humanity in neurology that we celebrate with the annual Ted Burns Award. Through his teaching, innovation, and drive to improve health care delivery, he is an inspiration for his students, neurologists, and people impacted by brain disease."

“Teaching and learning with my students, colleagues, and patients—and advocating for those with greater needs than my own—have been the most fulfilling aspects of my career,” said Quinlan upon receiving the award. “It is a great honor to receive this award and privilege to help lighten the load of our patients, their families, and our workmates."

You can hear more from Quinlan when he is recognized during a virtual salon on Humanism in Neurology at 7:00 p.m. CT on July 27, 2021. For more information and to register, visit AmericanBrainFoundation.org/events or email events@americanbrainfoundation.org. 

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In patients with relapsing forms of multiple sclerosis (RMS)

START WITH THE POWER AND EXPERIENCE OF TYSABRI

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

83%

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

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

IMPORTANT SAFETY INFORMATION WARNING: Progressive Multifocal Leukoencephalopathy (PML) TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include 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.

34

AANnews • July 2021

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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Director of Brain Health and Memory Center Opportunity at University Hospitals – Merritt Hawkins­—Cleveland, Ohio The Brain Health and Memory Center (BHAM) of the Department of Neurology in the Neurological Institute at University Hospitals is a national leader and heavily vested in programmatic expansion. We are looking to recruit faculty members at the level of Assistant Professor or higher to join our world-renowned faculty to contribute to the UH mission of commitment to clinical care, funded research, and education. To Heal. To Teach. To Discover.

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Community Information Located along beautiful Lake Erie and filled with tremendous opportunities for families and individuals alike, Cleveland is a perfect place to call home.

Enjoy Ohio’s second-largest city, its excellent schools, and low cost of living. A culturally rich and diverse community offering immediate big-city amenities, including an international airport and an array of shopping, dining, entertainment, and professional sports teams A thriving arts scene includes a world-renowned museum of art, the largest performing arts center outside of New York, and one of the top five orchestras in the world An abundance of outdoor recreation, including hiking, lakefront activities, and golfing Housing is available in urban or suburban locations with multiple independent schools and highly ranked public schools, including a challenging international baccalaureate program. University Hospitals is committed to Equal Opportunity and Diversity. Women, veterans, members of underrepresented minority groups, and individuals with disabilities are encouraged to apply. For immediate consideration please inquire with an updated copy of your

CV so we can discuss the position by phone. Also, inform me of your best available times to speak. I look forward to your reply and thank you for your review. Please do not delay as we anticipate a significant response. Please contact Alyssa Barraza at medcareers@merritthawkins.com or at (866) 406-0269and reference NEUR-130566 Desirable Orange County, California Location with Partner Buy-In Option – Fullerton Neurology and Headache Center – Orange County, California The Best Opportunity You Will See in Your Career–Desirable Orange County, California Location with Partner Buy-In Option. Bypass the bureaucracy and do your own thing.

You will have autonomy and decision-making control by joining the longest established and most respected neurology practice in Orange County. Develop your own subspecialty area or take pride in being a generalist.

As we have expertise in headache and MS, movement or memory disorders would be an especially good fit.

Consider our strengths: In the first group of three centers in California to be recognized by the NMSS as a Partner in Multiple Sclerosis Care. A member of the Consortium of MS Centers with an MS-certified physician assistant.

An on-site infusion suite. Participation in over 40 trials in MS. Board-certification in Headache Medicine since 2007.

A National Headache Foundation Children’s Headache Center. Clinical trials experience in children and teens.

Injecting Botox years before it was FDA-approved for migraine. Botox volume among the highest on the west coast. An active clinical trials program. Ongoing trials in MS, migraine, Parkinson’s disease, and Alzheimer’s disease. A teaching site for neurology residents and physician assistant students. What we seek: A confident, productive and compassionate recent trainee or mid-career clinician who can provide the highest possible quality of care and be comfortable working and innovating independently. What we offer: High-earning potential based on a competitive guaranteed salary with productivity bonuses. Generous benefits. Transparent and fair practice management. Oncall which is one-in-nine at only one 300-bed, highly rated hospital with all support services and which is located one block from our only office. Dedicated, high-quality and loyal support staff, including clinical trials coordinators, an infusion RN, and a scribe. A simple-to-use EMR system with on-site IT support. A comfortable, attractive and wellequipped office. Orange County, California is dynamic and diverse with distinct communities, wonderful

ethnic restaurants as well as opera, theatre, concerts, and museums. Fullerton has evolved from avocado and citrus groves into a desirable suburban city. Homes have large lots and backyard orchards, and many connect to equestrian trials which end at a riding ring with western and English horse shows. Mountain bikers and hikers will find miles of “gnarly” trails. Even better, you can live five minutes from the office and hospital. Public schools are among the best in California and nearby Cal State Fullerton has a perennial NCAA championship baseball team. Disneyland and the Angels and Ducks are a fifteen-minute drive. You can literally ski in the morning and surf in the afternoon.

The trailhead of a 12,000-foot peak and the Coachella valley desert are each an hour and a half away. Downtown Los Angeles and the beaches are a thirty-minute drive. Quality of life is unsurpassed. Contact jflorin@fullertoneuro.net.

Visit fullertonneurocenter.com and jackflorin.com.  AANnews® Classified Advertising The AAN offers a complete package of print, online, and in-person recruitment advertising opportunities.

Visit careers.AAN.com for all AAN options, rates, and deadlines.

Ad copy for the October 2021 print edition of AANnews must be submitted by August 1, 2021. The same deadline applies to changes/cancellations.

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

AANnews • June 2021 35

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JULY 1

Applications Open: AAN Research Program AAN.com/ResearchProgram

JULY 22

AUGUST 3 Registration Opens: Advanced Practice Provider Neurology Education Series AAN.com/APP

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

JULY 29

Neurology Virtual Career Fair Careers@AAN.com

SEPTEMBER 2

Early Registration Deadline: Advanced Practice Provider Neurology Education Series AAN.com/APP

SEPTEMBER 6– NOVEMBER 23

Advanced Practice Provider Neurology Education Series AAN.com/APP

JULY 30–31

Sports Concussion Conference AAN.com/SCC ESC: AMOD-Ad—Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

Access the 2021 Annual Meeting Anytime, Anywhere With 2021 Annual Meeting On Demand, you’ll get: ■ More than 300 hours of content ■ 140+ programs with syllabi from the live virtual meeting ■ 25+ exclusive bonus presentations to round out this comprehensive digital reference library ■ Integrated CME testing, with ability to claim CME through March 31, 2022

Learn more at AAN.com/AMOD