2020 December AANnews

VOLUME 33 · ISSUE 12 · DECEMBER 2020

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

RENEW YOUR MEMBERSHIP BEFORE DECEMBER 31 TO RETAIN ROBUST VIRTUAL OFFERINGS, STRONG COMMUNITY Renew Your Dues Before December 31 Don’t forget that it’s time to renew your AAN membership for 2021.

As the world continues to change around us in light of the COVID-19 pandemic, you can count on your Academy to be here for you to provide the same top-quality education, events, networking, and other programs and opportunities you’ve come to love—in new virtual formats that offer greater access and flexibility than ever.

By visiting AAN.com/dues today, you can be assured your AAN will be there for you come January 1 with the following essential education, science, and support: Unique online education opportunities to earn CME or continuous certification credits NEW virtual networking events and opportunities Continued on page 15

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Neurology on the Leading Edge Webinars Focus on COVID, Key Issues As part of the Academy’s ongoing commitment to providing guidance on the care of neurology patients affected

by COVID-19, as well as how the novel coronavirus pandemic is affecting the field of neurology overall, the AAN created Neurology on the Leading Edge, a new, quarterly live Zoom webinar opportunity available free to all AAN members.

Prepare for 2021 with Free Payment Changes Webinar

Smith

“At the beginning of the pandemic we recognized that neurologists all across America and in other countries were facing common challenges,” said A. Gordon Smith, MD, FAAN, Continued on page 15

28 2020 Year in Review for #AANadvocacy

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The AAN is offering a free webinar to help members understand payment changes in the Medicare Physician Fee Schedule effective January 1, 2021. The webinar will also review final Quality Payment Program reporting requirements for 2021, how to implement new procedure codes, and more. The live webinar will stream at 12:00 p.m. ET on December 15. The recorded webinar will be available five business days after the live webinar. Register at AAN.com. 

30 Need Year-end CME? These Will Help!

30 Pilot Program to Make

Continuum Articles Audible

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)].

ZEPOSIAÂŽ (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 · December 2020

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

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

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

memberservices@aan.com

12

Program Empowers Graduate to Tackle Disparities

13

Congratulations New Fellows of the American Academy of Neurology!

14

Leadership and Integrity Are Themes of New Member Spotlight Videos

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

Since graduating in 2017 from the AAN’s Diversity Leadership Program, Cumara O’Carroll, MD, MPH, could be the poster child for its success.

The AAN congratulates these members who were named prestigious Fellows of the American Academy of Neurology (FAAN).

The final two episodes of this year’s inspirational Member Spotlight videos are available for viewing.

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 AAN Holds Summit with Industry Roundtable Companies More than 50 representatives from more than 20 Industry Roundtable companies attended a recent virtual summit with AAN leaders, which was an increase from attendance at the 2019 in-person summit. Another summit will be held December 2 for discussions on telemedicine.

In Memoriam Join us in remembering members of the AAN and neurology community who have perished from COVID-19: Janice F. Wiesman, MD, FAAN

President’s Column

Outlook on Health Care Reform and the AAN’s Position After a whirlwind election season, it appears at this writing in mid-November that Joe Biden is president elect and will take office on January 20, 2021. Democrats maintained their majority (albeit reduced) in the House of Representatives, and control of the Senate will not be finalized until after the two runoff senatorial elections in Georgia in January.

What is 100-percent certain is our leaders must again take on health care reform in the coming months.

Any attempts to change health care policy will be informed by the hardships visited upon Americans due to the COVID-19 pandemic.

Millions of people were laid off temporarily or permanently and their employer-sponsored health care benefits were terminated.

Sudden loss of income made it difficult to impossible for people to pay for COBRA coverage, see their doctors, or continue their prescriptions. People also missed out on physician care because their doctors were closed during shutdowns or patients were afraid to risk coronavirus infection by going to their appointments.

Telehealth—a service the AAN has been advocating for the past few years, particularly with regard to compensation and nationwide acceptance by payors—came to the rescue for many providers and patients, and it could be an area where the Trump and Biden administrations find common ground. But telehealth is just a tool, not a policy.

The AAN took a neutral stance during the formation and deliberations over Obamacare. However, as the Trump administration announced it was going to create its own health reform alternative, the leaders of the Academy created a set of principles that were neither Republican nor Democrat, but focused on the care of our patients and support for our profession as neurologists. And so, before the battle is joined on Capitol Hill, I wish to reiterate the AAN’s Principles for Health Care Delivery: Access to high-quality health care and preventative care through insurance coverage for all, including those most vulnerable to health care disparities, regardless of pre-existing conditions

Appropriately value cognitive care services Limit administrative requirements and Stevens advocate for EHR functionality to ensure that physicians spend as little time as possible on low-value clerical work, and as much time as possible engaged in direct patient care Continue efforts to streamline EHR interoperability and reduce data blocking to allow any willing provider to participate in a qualified clinical data registry Improved valuation of patient-centered care setting alternatives including telemedicine and other innovative care models Improve efforts to reduce spending on pharmaceuticals and other key drivers of health care expense through cost transparency and permit the negotiation of drug costs

by Medicare Medical liability reforms to reduce the cost of premiums and defensive medicine Preservation of the physician-patient relationship including independent medical decision-making and patient access to needed treatments and education Protect access to neurology care in all settings, including small and solo practices Achieving these goals won’t be easy. Entrenched positions will need to be bridged. Special interests will need to compromise.

But we cannot continue to have the world’s most expensive health care without being the world leader in healthy outcomes and financial value.

Rest assured, we will continue to fight for the principles above and we will keep you updated on our progress along the way through AANnews and Capitol Hill Report on AAN.com and in your inbox. You can get engaged on issues by using #AANAdvocacy and responding to our advocacy email alerts where you can raise your voice to help sway Congress to do the right thing for the health and welfare of all Americans. 

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

AANnews • December 2020 11

Conferences & Community

Program Empowers Graduate to Tackle Disparities Since graduating in 2017 from the AAN’s Diversity Leadership Program, Cumara O’Carroll, MD, MPH, FAAN, could be the poster child for its success. Everything the program set out to do is exemplified in O’Carroll’s tireless efforts and subsequent accomplishments in tackling health care disparities both in the US and internationally.

“I am extremely grateful for having participated in the Diversity Leadership Program, with so many lessons learned as well as lasting friendships,” she said.

O’Carroll, who is a neurologist at the Mayo Clinic in Phoenix, AZ, credits the program with instilling in her a greater O'Carroll self-awareness, the importance of selfreflection and reflexive activities geared toward specific goals, and an increase in confidence. “I felt invigorated with a new sense of motivation, and I felt empowered to lead.” And lead she has.

One of O’Carroll’s passions is international work on health care disparities. Her focus is on both ischemic and hemorrhagic stroke in Uganda and stroke in HIV-infected individuals in sub-Saharan Africa, as well as the appropriate evaluation of comatose patients in limited-resource settings. “I usually go to Uganda for a month at a time to teach the neurology block to the internal medicine residents at Mbarara University of Science and Technology (MUST) while also providing mentorship and collaborating on research proposals,” she explained. “I was supposed to be there for the entire month of March [2020], but my trip got cut short because of the pandemic. When the residents found out that I had to return to the US earlier than anticipated, they asked me to give all the scheduled lectures in a one-week period. It was a bit of a whirlwind with multiple lectures a day, but they were engaged and eager to learn.”

For her work in Uganda, O’Carroll was awarded the Mayo Clinic Arizona Diversity and Inclusion Award in December 2019.

Since completing the Diversity Leadership Program, O’Carroll has expanded her focus to include health care disparities within the United States, as well. “I have been collaborating with former 2016 Diversity Leadership Program participant Dr. Michael Stitzer, a neurologist and the director of Native

American Neurology Service at Winslow Indian Health Care Center, with our efforts focused on better capturing acute stroke data in the Navajo Nation and the development of a stroke registry,” she said. “We are also in the process of applying for a grant with the intent of expanding telestroke services to the Navajo Nation.”

O’Carroll has also continued her heavy involvement in a medical and dental clinic she collaborated with St. Vincent de Paul to establish in 2013. “I have established a neurology clinic for a population of uninsured, mostly Hispanic patients and we (myself and other Mayo Clinic neurologists, residents, fellows) have been going once every month to provide free neurological care, which includes EMGs, nerve blocks, lumbar punctures, and more.”

Additionally, O’Carroll has participated in a leadership development program within her institution, she serves on the AAN’s International Subcommittee, and she was recently named the department diversity leader for neurology at Mayo Clinic AZ. “In my role as department diversity leader, I have started a Diversity & Inclusion/Anti-racism journal club, and invited several guest speakers to speak at our departmental Neuroscience Conference, including previous 2017 Diversity Leadership participant Dr. Roy Hamilton who spoke on ‘Diversity, Equity and Inclusion in Neurology: Where Are They Missing, Why They Matter, and How We Achieve Them.’”

Added O’Carroll, “The Diversity Leadership Program laid the foundation for several different pathways for positive impact, as well as enhancing my capacity to build strong professional networks and collaborations outside my institution.”

The Diversity Leadership Program is a crucial aspect of the AAN’s leadership diversification strategy intended to identify, mentor, and engage AAN members from underrepresented groups and supported in part

by Allergan, Inc.; Acadia Pharmaceuticals, Inc.; Eisai, Inc.; Genentech, a member of the Roche group; Neurocrine Biosciences; and Sanofi Genzyme. Learn more at AAN.com/DLP. 

12

AANnews • December 2020

Congratulations New Fellows of the American Academy of Neurology!

The AAN congratulates the following members who were named prestigious Fellows of the American Academy of Neurology (FAAN) between June and October 2020.

Daniel Ontaneda, MD, PhD, FAAN Tarso Adoni, MD, FAAN Alison M. Pack, MD, FAAN Mark J. Alberts, MD, FAAN Raul F. Pelli-Noble, MD, PhD, FAAN Eric Anderson, MD, PhD, FAAN Jose H. Posas, MD, FAAN Christine B. Baca, MD, FAAN John Probasco, MD, FAAN Pavan Bhargava, MD, FAAN Shabbir Saif Uddin Rangwala, MD, FAAN Leona D. Borchert, MD, FAAN Nina Yakovlevna Riggins, MD, FAAN Benjamin R. Brooks, MD, FAAN Maisha T. Robinson, MD, MS, FAAN Nitin Butala, MD, FAAN Anshu Rohatgi, MD, DM, FAAN Deirdre Donaldson, MD, FAAN Lara K. Ronan, MD, FAAN Massimo Filippi, MD, FAAN Ahmed H. Sadek, MD, FAAN Scott M. Friedenberg, MD, FAAN Teri Schreiner, MD, MPH, FAAN Smaranda Andreia Galis, MD, FAAN Osheik A. Seidi, MD, MRCP, ABIM, FAAN Sankar Prasad Gorthi, MD, FAAN Hitoshi Shinoto, MD, FAAN Janine L. Johnston, MD, FAAN Marc W. Slutzky, MD, PhD, FAAN Surindar Jolly, MD, FAAN Marco A. Soza, MD, FAAN Drew S. Kern, MD, FAAN Rebecca Spain, MD, MSPH, FAAN Omar Iqbal Khan, MD, FAAN I try Michael Strupp, MD, DO, FAAN David V. Lardizabal, MD, FAAN to insp peopleire Dexter Y. Sun, MD, PhD, FAAN Gregg MacLean, MD, FAAN have b who paralyzeen Easwar M. Sundaram, Jr., MD, FAAN Mia T. Minen, MD, FAAN ed.”

Camilo Toro, MD, FAAN MD, FAAN Publishing:Roberta 19 Brain Novakovic, 20 & Life Ad—Half Page Horizontal> AN Placed in AANnews William W. Tung, MD, MPH, FAAN Cumara C Barahona O'Carroll, MD, FAAN asin C 8.25 x 5.25 +0.125 bleed,h4C re Robert Tyndall, MD, FAAN Njide Okubadejo,g a MD,uFAAN Fatigue Expert Manag Ways to e Tired ness Stroke Recove 5 Survivo ry Helped rs: What Th Get Thro em ugh Cluste New Trer Headache to Curb atments the Pain

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Visit AAN.com/FAAN to see if you’re eligible for the FAAN designation— or encourage a qualifying colleague to apply. Applying for FAAN status is free, acknowledges exemplary work and achievements in the neurosciences, the clinical practice of neurology, or academic/administrative neurology; helps set you apart both within the Academy and throughout your professional career; and offers eligibility to serve on the AAN Board of Directors. 

COVID19 Heroe s

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Ruchi J. Wanchoo, MD, FAAN Andro Zangaladze, MD, PhD, FAAN Sarah Elizabeth Zauber, MD, FAAN 

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Conferences & Community

Leadership and Integrity Are Themes of New Member Spotlight Videos The final two episodes of this year’s inspirational Member Spotlight videos are available for viewing. AAN President James C. Stevens, MD, FAAN, has interviewed members living the values of the AAN in inspiring ways.

Aaron Berkowitz, MD, PhD, is the founding director of global health at the Kaiser Permanente Bernard J. Tyson School of Medicine and leader of the development of the school’s neurology curriculum. As a consultant to Doctors Without Borders, Berkowitz is involved in humanitarian collaborations and neurology education around the world, including in Haiti, Malawi, Vietnam, and the Navajo Nation.

Stevens highlights how Berkowitz’s efforts tie closely to AAN values, particularly the value of Leadership: We guide, inspire, and empower members, patients, and other stakeholders to make a positive difference in their own lives and the lives of others in the neurology community, and to contribute to the Academy mission.

Deanna Saylor, MD, is a neuro-infectious disease and neuroimmunology specialist at the Johns Hopkins Hospital with special interest in the neurological complications of HIV infection. She also specializes in global health and neurology.

Saylor is 2020 Practice Research Training Scholarship recipient, which is helping to fund her work in Zambia, where she has ongoing research collaborations. Her inspiring story

and lessons learned reflect the AAN’s value of Integrity: We set and maintain the highest ethical standards for ourselves and our programs, products, and services.

These and previous videos that show how members are demonstrating AAN values can be seen in a playlist on the AAN YouTube channel at YouTube.com/AANchannel. 

AAN Staff Singled out for Great Performers Award Ten AAN employees were recently recognized as recipients of the 2019 Great Performers Award. In a virtual ceremony, President James C. Stevens, MD, FAAN; CEO Mary E. Post, MBA, CAE; and members of the AAN Board of Directors and executive staff honored these staff members for their stellar commitment to carrying out the mission and vision of the Academy.

Top row: Matt Bares, Manager, Technology Solutions Amanda Doering, Managing Editor, Continuum® Carly Ferry, Senior Manager, Digital Content Chris Hansohn, Senior Web Developer Sarah Parsons, Manager, Writing and Editing Bottom row: Meagan Pick, Manager, Annual Meeting and Regional Conferences Publications Bobby Rook, eLearning Program Manager Dave Showers, Senior Manager, Advocacy Development Erica Slack, Manager, Marketing Communications Project Management Becky Wolf, Practice Management Solutions Program Manager

14

AANnews • December 2020

Neurology on the Leading Edge Webinars Focus on COVID, Key Issues Continued from cover chair of the AAN Education Committee and neurology department chair at the Virginia Commonwealth University. “The concept for Neurology on the Leading Edge came from a collaborative effort to support medical student education in the US and Italy.”

front lines and in their daily lives as neurologists and medical educators. Smith introduced the session along with Charlene Gamaldo, MD, FAAN, and Rachel Marie E. Salas, MD, FAAN, served as moderator.

As Smith explained, those involved in the project “immediately saw an opportunity to share ideas about an important topic in a highly engaging and conversational fashion that brought together neurologists and all members of our care team from diverse locations and practice settings.”

More than 550 participants joined Vivian S. Lee, MD, PhD, MBA, president of health platforms at Verily and author of “The Long Fix: Solving America’s Health Care Crisis with Strategies that Work for Everyone,” on September 22 for her talk on “Post Pandemic Neurology: Solutions for Lasting Change in Health Care.” Lee discussed the future of health care in America and why our system is failing the “COVID stress test.” Smith, along with AAN President Elect Orly Avitzur, MD, MBA, FAAN, guided the talk.

If the pandemic was preventing neurologists from being with friends and colleagues in person, Neurology on the Leading Edge was an attempt to bring together the larger community to engage in and discuss topics that impact neurology patients and the profession in a personal and meaningful way.

Two highly successful events have been held to date, with more planned in the coming months.

On May 4, 1,800 medical students, residents, practitioners, researchers, and academicians participated in “COVID-19 Lessons Learned by Italian Neurologists,” led by Guiseppe Lauria Pinter, MD, and Leonardo Pantoni, MD, PhD, both professors of neurology at the University Milan. Pinter and Pantoni shared what they learned from their work on the

Added Smith, “Our hope is that Neurology on the Leading Edge will provide timely and highly relevant information in a very engaging and entertaining fashion, and that members who participate can be part of the conversation.”

Recordings of both webinars are available on the AAN’s COVID-19 Neurology Resource Center and on the AAN YouTube channel at Youtube.com/AANChannel, where more than 2,000 members have already viewed this important resource. Look for information on future Neurology on the Leading Edge webinars at AAN.com. 

Renew Your Membership Before December 31 to Retain Robust Virtual Offerings, Strong Community­ Continued from cover Up-to-date information on breakthrough scientific research on the new Scientific Highlights platform

Representation of your interests at the federal/state levels

Valuable clinical practice guidelines

Special pricing on AAN products, services, or meetings

The latest news relevant to the profession

Exclusive access to AAN.com member-only resources

PODCAST

Find the full list of exclusive member benefits at AAN.com/benefits. For more information, contact AAN Member Services at memberservices@aan. com, (800) 879-1960, or (612) 928-6000 (international), or use the chat feature on AAN.com. 

Neurology ® Podcast:

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

AANnews • December 2020 15

In patients with relapsing forms of multiple sclerosis (RMS)

START WITH THE POWER AND EXPERIENCE OF TYSABRI

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

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

1,2

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

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

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

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

MORE THAN

APPROXIMATELY

200,000

15 YEARS OF EXPERIENCE

NEW PATIENTS

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

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

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

PATIENTS TREATED

1 IN 3

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

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

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

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

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

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

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

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

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

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

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

1.

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

2.

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

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

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

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

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

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

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

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

4.

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

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

5.

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

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

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

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

1/10,000

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 2:

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

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

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2 9 4 3 2 1

7 3

2 <1 <1

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**

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=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.

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pharma Ad 5 <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 Study CD3 (Maintenance Study)

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

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

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

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

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

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

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

8.

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

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

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

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

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

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

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

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

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

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

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

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

17.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pharma Ad

Tools & Resources

What Is Informatics?

Informatics. It’s not typically very long into any discussion about health care quality before this word makes its way into the conversation. But what exactly is informatics? Why does “informatics” come up so frequently in articles and discussions about the quality and safety of health care? More importantly, what do you―a neurology provider or business administrator―need to know about informatics?

Simply put, informatics is the science concerned with the use of computer-based technologies to help humans acquire and apply the knowledge necessary to optimize human health. As scientists, health professionals, and health care administrators, we know that to improve health outcomes, we need to learn all we can about health and illness, and continually find new and better ways to prevent, detect, and treat it. We need to continually assess how well we apply what we know, and whether the consistent and skillful application of new knowledge results in the desired outcomes.

To do this, scientists and health care professionals collect data and turn these data into actionable knowledge. This is where the science of informatics comes in. Informatics conceives of the knowledge acquisition process as a series of core activities that computer-based technologies can be designed to support.

To learn more about the Axon Registry and to enroll, visit AAN.com/Axon. 

Practice to Data

Aquire Data

Disseminate Knowledge

Generate Information

Generate Knowledge

ge

e dg

Apply Knowledge

Kno w le

Data to K n o w l ed

Based on: The Knowledge Object Reference Ontology (KORO): A formalism to support management and sharing of computable biomedical knowledge for learning health systems. Flynn AJ, Friedman CP, Boisvert P, Landis-Lewis Z, Lagoze C. Learn Health Syst. 2018;2(2).

ormance f r e to P

These activities include capturing data, turning data to information, converting information to knowledge, applying new knowledge, and capturing data about the application of this knowledge to start the cycle all over again (see illustration). The science of informatics recognizes that while the human brain is really good at a lot of things, it has limitations. Informatics technologies are designed to support these limitations.

Informaticians develop technologies to enable the efficient capture, storage, and retrieval of data.

They develop technologies to turn these data into actionable knowledge, and technologies to make this knowledge available to scientists and health practitioners at the time and in the place where they need it most.

The Axon Registry ® is an example of informatics in action.

Providers capture clinical data in their EHRs during the routine delivery of neurologic care. This data is then transmitted to the Axon Registry, where it is fully de-identified, pooled, aggregated, and analyzed. The registry calculates how often patients receive the care believed to produce optimal outcomes based on the field’s current, best knowledge (summarized in clinical practice guidelines) and quantified via quality measures.

Data in the registry is also used to generate new knowledge about whether current, known best practices generate the expected outcomes across all subtypes of patients to whom a guideline applies. These types of analyses would be extremely difficult, time consuming, and costly to perform without informatics technologies. The ultimate goal of Informatics―the science concerned with how the human brain acquires and applies knowledge―focuses on developing computer-based technologies to maximize and extend the incredible capacities of the human brain.

AANnews • December 2020 23

Tools & Resources

New Value-based Care Resources: Care Model Case Studies For years, providers have been hearing about value-based care and innovation in care delivery. Some providers may associate value-based care with the Centers for Medicare & Medicaid Services’ Quality Payment Program and regulatory requirements, while others may not even realize they already participate in activities that fall under the broad “value-based care” umbrella within their practice or institution. The AAN is developing a care model case study library to help demystify the daily operations of certain care models and describe how neurology providers might fit into these different care and payment models.

Two case studies related to telemedicine are the first features in the care model library. The first case study explores working for a private telemedicine company, while the other looks at working in a statewide public teleneurology program. While much has and continues to change in the telemedicine space in the last year due to the COVID-19 pandemic, these models are likely more relevant to members than ever. The case studies explore how a neurology provider works within the model, including how they see patients, how they are paid, and implications and value of the model to the provider, their patients, and the local health care system. Additional case studies related to other novel care models will be forthcoming.

To explore these case studies, visit AAN.com/CareModelCases.

Contact practice@aan.com if you have questions or are interested in participating in a care model case study in the future. 

Bill Geist Describes Life with Parkinson’s Disease in Latest Brain & Life Former CBS correspondent Bill Geist never let Parkinson’s disease slow his career in journalism or put a dent in his optimistic view of life. He and his son Willie Geist, anchor of NBC’s Sunday Today and co-anchor of MSNBC’s Morning Joe, talk about Bill’s distinctive approach to his diagnosis and how they both have supported organizations that help people with disease. During the pandemic, they’ve worked extra hard to make every day “good, memorable, and joyful.”

People who recover from COVID-19 report lingering neurologic symptoms such as fatigue, mental fogginess, and sustained loss of smell and taste. A feature story examines this phenomenon and offers advice for managing and overcoming these symptoms.

Another feature provides an update on the state of COVID-19 vaccines as well as a primer on vaccines in general—how they work, the different types, side effects, and what people with neurologic disorders need to know before getting vaccinated.

In other departments, stories look at how patient organizations and advocacy groups are connecting with their

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AANnews • December 2020

communities during the pandemic, how to manage psychosis in patients with dementia, and how diet affects Parkinson’s disease.

Brain & Life magazine is free for AAN members in the United States to hand out to patients, who also can subscribe for free. If you would like to adjust the number of copies you receive for your patients or update your clinic address, email BeGreen@WasteFreeMail.com.

All members have online access to the magazine articles and additional resources at BrainandLife.org. Please share the website with your patients. 

Prevention What to Know About COVID-19 Vaccines Virtual Suppor How and Wheret Patients Find Community COVID-19 The Road to Recovery

We try to make every day with Parkinson’s disease good memorable, , and joyful.”

— TV CORR ESPOND

ENTS BILL AND WILLI E GEIST

DECEMBER

2 0 2 0/JA N UA

RY 2 0 2 1

April 17 – April 22 • San Francisco In-person and Virtual

SAVE THE DATE SAN

FRANCISCO

Tools & Resources

Neurology: Clinical Practice Explores Headache, Transient Ischemic Attack, and Functional Neurologic Disorders The new issue of Neurology ® Clinical Practice features editorials “Functional Neurologic Disorders: Bringing the Informal and Hidden Curriculum to Light,” by Laura Strom, MD, and “Smartphone Use and Headaches: Are We Ready to Accept a Link?” by Heidi Moawad, MD.

Volume

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Other topics include spinal cord transient ischemic attack, treatment of migraine in patients with CADASIL, and an American Headache Society member survey on sphenopalatine ganglion block in primary headaches.

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

RESEAR

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Spinal co rd a series of transient ischemi c attack: spontane Ins ous spina l cord inf ights from REVIEW arction 482 Conside rin deficit hy g learning disabilit pe ies and att neurode ractivity disorder ention generativ e disease when assessing for 522

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Treatme nt of migra A system ine atic review in patients with CADASIL and metaanalysis : 490

MEM: 18 APP Recruitment Ad Ad—Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

A STRONGER TEAM MEANS STRONGER CARE

Strengthen your ADVANCED PRACTICE PROVIDER’S knowledge and skills in neurology with special, reduced rate AAN memberships.

Sign your team up today at AAN.com/view/CareTeam

Policy & Guidelines

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

Forecast for the Future Under Divided Government Staff Perspective by Derek Brandt, JD, AAN Director of Congressional Affairs After all the campaigning, money, and predictions, the 2020 election resulted in the likely continuation of divided control of the government, with a Democrat-controlled House, a likely Republican Senate, and a recently called Democrat president in the White House. The turnout for the election was recordbreaking, yet the results were surprising to many, due in large part to inaccurate polling on the state and national levels.

Overall, incumbents supported by the AAN’s political action committee BrainPAC had a very successful night. BrainPAC contributed to roughly 100 incumbents running for re-election in 2020, and more than 90 percent of those won re-election.

During this election cycle, BrainPAC also contributed to six nonincumbents, which included four physicians and AAN member Alexandra Owensby, DNP. Unfortunately, of these, it is likely that only Rep. Rodger Marshall, MD, was successful. He will be seated as a senator for Kansas starting in January 2021.

It will take a while to fully understand the ramifications of the 2020 election, but several immediate effects on AAN advocacy are evident. Prior to inauguration day, Congress must pass legislation to fund the government beyond December 11. In recent years, this task has proven to be easier said than done.

This spending bill may also include other health care provisions, such as providing financial relief for physicians and other health care providers, which is discussed further below.

Any year-end legislative package may also include additional COVID-19 relief that would build upon the trillions of dollars already authorized by Congress. For months there has been an appetite for more COVID-19 relief, but until now negotiations had been unsuccessful. “We need another rescue package,” said Senate Majority Leader Mitch McConnell the day after the election. “Hopefully the partisan passions that prevented us from doing another rescue package will subside with the election and I think we need to do it and I think we need to do it before the end of the year.”

Once the president and Congress are seated, the clock will begin on the first 100 days of the new presidency, which are the most important for each term. Yet, with such a close election, the president may lack a mandate of the people sufficient to pressure political allies and opponents into acting on their signature initiatives. Combined with divided control of Congress and modern partisan politics, it is unclear whether any significant legislative reforms will be possible in 2021. This makes it more likely that the president will act unilaterally on many issues through executive orders and promulgating new regulations. Meanwhile, Congress may be forced to settle for only advancing smaller incremental reforms, as Democrats and Republicans will likely continue to struggle to find common ground on major policy areas such as the Affordable Care Act and non-health care issues relating to climate change, voting rights, criminal justice reform, and taxes. 

AANnews • December 2020 27

Policy & Guidelines

2020 Year in Review for #AANadvocacy

30+ 60+ COMMENT LETTERS

ADVOCACY POSITION STATEMENTS updated on

COALITION SIGN-ON LETTERS

stroke, medical cannabis, and sports concussion

to government agencies and Congress

EVALUATION & MANAGEMENT SERVICES

Advocated to protect planned implementation of new coding and payment structure in 2021 without modification or delay

250+

VIRTUAL AAN MEETINGS

with congressional offices

NEUROLOGY ON THE HILL

211

NEUROLOGY OFF THE HILL

2,500+

AAN members used the Advocacy Action Center to contact their policymakers

LEGISLATIVE SUMMIT

95 28

AAN members advocated to lower out-of-pocket medication costs for Medicare patients, reduce prior authorization regulatory burden, and increase research funding

members advocated for telehealth flexibilities and to protect E/M coding changes, meeting with nearly every US Senate office

AANnews • December 2020

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members participated in relationship building and telehealth advocacy

#AANadvocacy

Hey, Siri!

COVID-19 ADVOCACY Maintaining patient access to care during the pandemic was a key advocacy priority. The AAN urged the Trump administration and Congress to permit telehealth flexibilities early in the pandemic. The public health emergency was declared in March 2020 and the Department of Health and Human Services lifted restrictions for telehealth in Medicare. The Academy continues to advocate for telehealth flexibilities to be extended beyond public health emergency.

Medical Research

Provider Workforce

Funding for Personal Protective Equipment

AAN COVID-19 Advocacy Issues

Medication Access Regulatory Burden Relief

Medical Licensure & Liability Flexibilities

Play the latest Neurology Minute episode. neurology MINUTE

TM

Financial Support for Physician Practices

Telemedicine & Payment Parity

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

Subscribe to the Neurology Minuteâ&#x201E;˘ podcast and program your Siri, Alexa, or Google Assistant.

Education & Research

Need Year-end CME? These Will Help!

Valued AAN members have free and discounted access to a variety of convenient online CME and self-assessment resources.

Browse all programs and get started fulfilling your requirements today at AAN.com/learn.

Free with Membership Neurology Question of the Day Earn up to 29 self-assessment CME per year by answering short daily questions on topics from multiple neurology subspecialties.

NeuroSAE® Earn up to 8 self-assessment CME per exam with the AAN’s popular online self-assessment resource.

NeuroLearnSM Learn about relevant clinical and practice topics while earning a range of CME credits with the AAN’s convenient suite of exclusive online education courses.

Neurology ® and Neurology® Podcast Earn CME credits by reading two editor-selected articles per week and completing corresponding online exams.

Earn .5 CME credits per podcast (up to 24 CME per year).

2019 Annual Meeting On Demand Earn up to 242.75 CME with this CME-accredited comprehensive digital library of presentations from the 2019 AAN Annual Meeting.

Discounted with Membership NEW! Virtual Conferences On Demand Listen to recordings on demand of the 2020 Sports Concussion Conference, recent AAN Fall Conference— which will be available later this month—and the Advanced Practice Provider Neurology Education Series. The Sports Concussion Conference offers up to 4.5 CME, the Fall Conference offers up to 17 CME, and the APP Education Series offers up to 6 CME. NeuroReady Preparing for the neurology boards? Up for recertification?

Looking for a solid foundational knowledge in neurology?

Get ready with the AAN’s convenient online NeuroReady courses. Choose from the Board Prep Edition (no CME offered), Continuing Certification Edition (up to 15 selfassessment CME), and new Advanced Practice Provider Edition (up to 8 self-assessment CME).

Continuum® and Continuum® Audio Earn up to 20 AMA PRA Category 1 Credits™ toward self-assessment CME with each issue of the AAN’s official CME journal. Supplement with Continuum Audio to listen to conversations with Continuum authors and earn CME. Practice Management Webinars Earn 2 AMA PRA Category 1 Credits™ CME or CMPE with each pre-recorded webinar. 

Apply for 2021 Neuro-oncology Certification Exam

Pilot Program to Make Continuum Full Print Articles Audible

Applications are now being accepted for the United Council for Neurologic Subspecialties (UCNS) Neurooncology Certification Examination. Physicians who achieve subspecialty certification through the UCNS have met the requirements and standards of knowledge set by experts in the subspecialty.

In answer to member requests for audio book-style readings of the Continuum: Lifelong Learning in Neurology ® articles, the AAN is launching a pilot program of readings of the full articles from the October and December 2020 issues, as well as the February 2021 issue. Different from Continuum® Audio, these recordings are read verbatim from the print articles by Michael Kentris, DO, a neurologist at the Clinical Neuroscience Institute in Dayton, OH. The audio files are available to all Continuum® subscribers in the AAN’s Online Learning Center along with a survey.

Subscribers are encouraged to submit the survey with their feedback after listening to the articles. 

The deadline for applications is March 1, 2021. The examination will take place during the week of September 13–17, 2021 and will be administered online with virtual live proctoring.

For more information, visit UCNS.org. 

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AANnews • December 2020

Get Current on Neuro-oncology Topics Covered in New Continuum Continuum: Lifelong Learning in Neurology® presents the latest update in neuro-oncology in its new issue.

“Outcomes, including survival, for several types of primary brain tumors have improved with multi-modality treatment plans,” according to Tracy T. Batchelor, MD, MPH, guest editor of the latest issue. “The management of patients with brain metastases is evolving rapidly with improved outcomes in patients treated with targeted therapies and immunotherapies. Neurotoxicity and cognitive function become important considerations in these subpopulations with longer survival.”

Batchelor

The robust issue’s topics include: Adult Gliomas / Howard Colman, MD, PhD, FAAN Central Nervous System Lymphomas / Christian Grommes, MD Nonmalignant Brain Tumors / Rimas V. Lukas, MD; Maciej M. Mrugala, MD, PhD, MPH, FAAN Familial Nervous System Tumor Syndromes / Roy E. Strowd III, MD, MEd; Scott Plotkin, MD, PhD

Pediatric Brain Tumor / Sonia Partap, MD; Michelle Monje, MD, PhD

Neurotoxicity of Cancer Therapies / Jorg Dietrich, MD, PhD, FAAN Palliative and Supportive Care in Neuro-oncology / Deborah A. Forst, MD

Metastasis to the Central Nervous System / Adrienne Boire, MD, PhD Paraneoplastic Disorders of the Nervous System / Eudocia Q. Lee, MD, MPH; Eoin P. Flanagan, MBBCh

Evaluation and Management Codes for Outpatient Neurology Services in 2021: Changes to 99202–99215 / Bruce H. Cohen, MD, FAAN; Neil A. Busis, MD, FAAN; Raissa Villanueva, MD, MPH, FAAN; Luana Ciccarelli, CPC, CRC

Neurologic Complications in Patients with Cancer / Eudocia Q. Lee, MD, MPH

The issue includes a postreading self-assessment and test with the opportunity to earn up to 20 AMA PRA Category 1 Credits™ toward self-assessment CME. AAN members pay only $399 per year for a subscription to Continuum® and Continuum® Audio. Subscribe now by contacting Wolters Kluwer at (800) 361-0633 or (301) 223-2300 (international) or visit Shop.LWW.com/continuum. AAN Junior members who are transitioning to neurologist memberships are eligible to receive a 60-percent discount on the already low member rate for the Continuum and Continuum Audio subscription. 

Are You Getting Your AANe-news?

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

It’s Not Spam... It’s AANe-news!

AANnews • December 2020 31

American Brain Foundation

Spotlight: Next Generation Research Grant Alumni Give Back Supporting early career researchers and their innovative work is a gift that keeps on giving. No one understands this better than these three alumni of the American Brain Foundation’s Next Generation Research Grants program. In celebration of the program’s 28th year, we share the stories of three alumni who have progressed from early-career researchers to valued mentors.

Merit Cudkowicz, MD, MSc: Supporting Research, Paying It Forward Celebrated ALS researcher and early recipient of a Clinical Research Training Scholarship Merit Cudkowicz credits the Cudkowicz grant program with helping her bring new treatments forward to help patients. “I still remember the day that I got the American Brain Foundation award in 1996,” she said.

As one of the Foundation’s first awardees, she had the opportunity to meet members of the advisory and review committees and talk one-on-one with these leaders in neuroscience. “Not only did the grant help launch my career— it was one of my first grants ever—but meeting all those people was phenomenal because they became mentors.”

Today, Cudkowicz is chair of neurology at Massachusetts General Hospital and a member of the American Brain Foundation’s Research Advisory Committee, where she provides the same mentorship that she once received. “It is an honor to be part of the American Brain Foundation and to give back and support young investigators excited about research careers in neurology.”

Shafali Jeste, MD, FAAN: Stopping Autism Before It Starts Autism was being diagnosed at higher rates when Shafali Jeste, MD, FAAN, entered medical school—but physicians couldn’t tell parents why. Jeste formulated Jeste questions about how genetic syndromes such as tuberous sclerosis complex (TSC) had strong links to autism. “We could diagnose babies with tuberous sclerosis complex before birth with ultrasound,” she recalled, “but we knew nothing about their early brain development and the high risks of developing autism.”

During her residency, Jeste received a Clinical Research Training Scholarship to understand early brain development in babies with TSC. At UCLA, she followed up this initial investigation with a larger multisite study that identified an early predictor of autism for babies with TSC. These findings led to the first multimillion-dollar, multisite clinical trial focused on early interventions for autism.

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AANnews • December 2020

Now an associate professor in psychiatry, pediatrics, and neurology at UCLA, and an officer on the Foundation’s board, Jeste is quick to recognize the contributions the AAN and Foundation have made to her career. “The Foundation holds a very special place in my heart because I would say, actually, that the Foundation and AAN were what really launched my career.”

Chadwick Hales, MD, PhD: From Alzheimer’s Research to Broad-based Application In 2009, Chadwick Hales, MD, PhD, received a Clinical Research Training Scholarship from the American Brain Foundation to Hales study electrical activity in neurons with Alzheimer’s disease. “The goal was to really try to understand different pathologies, such as changes that occur in Alzheimer’s disease, and then use that as a way to potentially develop therapeutics,” he said.

More than 10 years later, the initial research has grown from “a pie in the sky idea” that focused on an Alzheimer’s question, to laying the foundation for understanding other disorders like ALS and frontotemporal dementia. “That’s why this investment and these awards [are] so important, because even though it’s one little piece, it can have broad-based applications, especially if you hit on one of those areas that makes a huge difference for patients,” he said.

A few years after he received the grant, Hales was approached to be part of the AAN Research Program Subcommittee.

“Of course, I couldn’t say no because I’m really interested in passing it on and training that next generation.” As part of the committee, Hales reviews research proposals to ensure that the best and brightest early-career scientific investigators can pursue their innovative research and advance the field.

The American Brain Foundation was founded by the American Academy of Neurology to bring researchers and donors together in the fight against brain disease. Next Generation Research Grants fund the innovative research of early-career investigators, encouraging passion for research and laying the groundwork for future success. Thanks to its collaboration with AAN, whose Science Committee selects the recipients, the Foundation has been able to support 28 early-career researchers this year. Visit AmericanBrainFoundation.org to learn more. 

YOUR SUPPORT CAN CHANGE LIVES.

Finding a cure for brain diseases and disorders will change the lives of millions of people. Your donation supports the researchers working each day towards life without brain disease.

Every dollar donated brings us one step closer to a cure.

Make your donation today at AmericanBrainFoundation.org/Give.

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Application Deadline: UCNS Fellowship Training Program Accreditation UCNS.org/Accreditation

DECEMBER 4

JANUARY 1

Applications Open: UCNS Clinical Neuromuscular Pathology Certification UCNS.org/CNMPcertification

Registration Deadline: RITE® AAN.com/RITE2021

DECEMBER 10

Futures in Neurologic Research Webinar For Trainees: “Networking & Celebration” learning.aan.com

DECEMBER 15

Free Webinar: Prepare for 2021 Payment and Policy Changes AAN.com

DECEMBER 18

Cancellation Deadline: RITE AAN.com/RITE2021 CareerCenter: 20 NCC Ad, halfpage Placed in AANnews, Brain&Life 8.25 x 5.25 +0.125 bleed, 4C

The American Academy of Neurology is proud to offer

THE #1 CAREER CENTER FOR NEUROLOGISTS

FIND A JOB

RECRUIT TOP TALENT

Learn more! Careers.AAN.com

FEBRUARY 1

Applications Open: UCNS Neurocritical Care Certification UCNS.org/NCCcertification

FEBRUARY 9–17

RITE® Administration Dates AAN.com/RITE2021

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

INDICATIONS AND USAGE: GOCOVRI is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

CONTRAINDICATIONS: Contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2 WARNINGS AND PRECAUTIONS: Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported in 4% vs 1% of patients treated with GOCOVRI or placebo, respectively. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (eg, driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence.

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

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

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

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

Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. If possible, avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of such urges, and to consider dose reduction or stopping GOCOVRI treatment.

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

GOCOVRI was evaluated in 2 double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients). The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for 1 week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Study 1 was stopped prematurely unrelated to safety, with 39/100 patients (safety population) treated with GOCOVRI for 24 weeks.

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

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

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

hyperplasia—all male (6%, 2%) Respiratory, thoracic, and mediastinal disorders: cough (3%, 0%). Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia.

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

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

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

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

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

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

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

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

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

Geriatric Use: In Phase 3 clinical trials, the mean age of patients at study entry was 65 years. Of the total number of patients in clinical studies of GOCOVRI, 46% were less than 65 years of age, 39% were 65-74 years of age, and 15% were 75 years of age or older.

Hallucinations and falls occurred more frequently in patients 65 years of age or older, compared with those less than 65 years of age. No dose adjustment is recommended on the basis of age. GOCOVRI is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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

Overdosage: Deaths have been reported from overdose with amantadine immediaterelease. The lowest reported acute lethal dose was 1 g of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction, including increased BUN and decreased creatinine clearance, can occur. Central nervous system effects that have been reported with overdose include agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor, disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has occurred with amantadine overdose. For acute overdosing, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary. The excretion rate of amantadine increases with acidification of urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes. Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias. Monitor blood electrolytes, urine pH, and urinary output. Although amantadine is not efficiently removed by hemodialysis, this procedure may be useful in the treatment of amantadine toxicity in patients with renal failure.

References: 1. GOCOVRI® (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2020. 2. Hauser RA, Pahwa R, Wargin WA, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77-88. 3. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS- 5102 (amantadine) extended-release capsules for dyskinesia in Parkinson disease. CNS Drugs. 2018;32(4): 387-398. 4. Data on file. Adamas Pharma LLC, Emeryville, CA.

Adamas and Gocovri are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies. © 2020 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved.

GOC-0728 09/20

NIGHTTIME DOSING DOSING NIGHTTIME

DAYTIMEDAYTIME COVERAGE COVERAGE

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

GOCOVRI® COULD MEAN THE DIFFERENCE

BETWEEN GETTING UP

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

Not an actual patient.

31% DECREASE IN DYSKINESIA 36% DECREASE IN OFF TIME 29% INCREASE IN GOOD ON TIME

10.1-point reduction in UDysRS score (-17.7 GOCOVRI® vs -7.6 placebo) 3,4†

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

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

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

Visit GocovriHCP.com to learn more.

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

INDICATION GOCOVRI® (amantadine) extended release capsules is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopabased therapy, with or without concomitant dopaminergic medications.

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

WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

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

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

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

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

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

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

Adamas and Gocovri are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies. © 2020 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved. GOC-0728 09/20