2020 October AANnews

VOLUME 33 · ISSUE 10 · October 2020

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

UPCOMING VIRTUAL FALL CONFERENCE PROGRAM HIGHLIGHTS Be sure to visit AAN.com/20FC before November 2 to secure the best rates for the Fall Conference, to be presented via a virtual format this November 6–7. Registration includes access to the live virtual event, session recordings, and program materials for up to one year, as well as up to 17 CME. As always, the Fall Conference will provide the timeliest clinical updates from noteworthy experts on the hottest topics in neurology, as well as a prime opportunity to fulfill end-of-year CME requirements.

November 6–7, 2020 Register at AAN.com/20FC

The program includes: Keynote addresses on COVID-19 and Health Care Disparities Neurology Update programs covering:

Epilepsy Headache Neuro-ophthalmology Dementia Multiple Sclerosis Movement Disorders Stroke

Continued on page 25

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Axon Registry Participants Share How They Benefit

Submit Your Best Science

by October 19

The AAN is committed to providing the best service for neurologists across the communities we serve. Here in Minneapolis, we don’t have to go far to ask staff at two of the largest neurology clinics in the country how the Axon Registry®— in which their practices have been enrolled for four years— helps improve quality and reduces administrative burden.

We want to see your science! Visit AAN.com/21Abstracts before October 19 to submit your breakthrough research to the best platform for getting your work noticed by your neurology peers from around the globe—the 2021 AAN Annual Meeting, set for April 17–22, 2021. Abstracts will be accepted in all subspecialties and career levels for either virtual or in-person presentation.

Gain exposure for your work with a chance to have your research picked up by major media outlets around the globe, including the New York Times, USA Today, CNN, and more!

Kathy Vinson, quality improvement manager at the Minneapolis Clinic of Neurology, discussed how the Axon Registry’s data helps her determine how quality improvement projects are initiated at her practice. “At the beginning of the year, I formulate ideas for projects after Continued on page 35

26 October 21 Application Deadline

Approaching for 2021 AAN Awards

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The submission fee is $100 for AAN members and $200 for nonmembers. Submission is free for residents and medical students. For more information, contact Laura Southwick at science@aan.com. 

38 Stumped? Send Your Practice-related Questions to practice@aan.com

April 17– April 22 • San Francisco

42 Frampton Comes Alive in Latest Brain & Life

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 · October 2020

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

the CEO: Perspectives on 14 From Leading the AAN

AAN Chief Executive Officer Mary E. Post, MBA, CAE, shares her philosophy and approach to leading the Academy’s management and staff.

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

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

memberservices@aan.com

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

16

Deadlines Approaching for Four Unique Leadership Opportunities During these unprecedented times, the AAN is pleased to announce that it will continue to offer its premier leadership development programs over the coming year.

28 Special Edition

Capitol Hill Report: Election An AAN member describes how COVID-19 has affected her first campaign for public office, one of several congressional races supported by contributions from BrainPAC.

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 SIGN of the Season for Medical Student Groups

Webinar Highlighted ‘APPs in Action’

It’s the time of the year to re-register or sign up for a Student Interest Group in Neurology (SIGN) chapter for medical students at your institution. Learn more at AAN.com/tools-and-resources/ medical-students/sign-toolkit.

The Consortium of Neurology Advanced Practice Providers’ “APPs in Action” webinar on August 28 highlighted APP members doing important work in and outside of neurology. Three APPs described their experiences running for Congress, serving as president of a human rights organization, and serving on the COVID-19 front lines and shared how their work as a neurology APP enhanced these endeavors. There were 27 participants and a survey showed all participants rating the event as either “excellent” or “good.”

MAKE A DIFFERENCE FOR RESEARCHERS IN YOUR FIELD.

Give back to the field with a gift to the American Brain Foundation.

The American Brain Foundation was founded by the AAN as the premier foundation that promotes and invests in research across the whole spectrum of brain disease. With the help of AAN members, we continue our relentless pursuit of discovery research that will lead to improvements in diagnoses, treatments, and ultimately cures for brain diseases.

Donate today at AmericanBrainFoundation.org/Give

President’s Column

Giving You the AAN You Need, This Year and Next

Stevens

It’s October, the month when we typically begin our membership renewal campaign. But it’s a very different October than in past years for you and for the AAN. We’ve been fighting the effects of a deadly and disruptive pandemic. You, on the front lines, have seen seismic changes in how your practices and clinics and hospitals have operated. Researchers have seen their vital work disrupted. Many of you have put your lives on the line without adequate safety equipment and precautions as you’ve helped treat people afflicted with COVID-19 or your regular neurology patients. Many practices have suffered financially due to mandated closures and unwillingness of patients to risk venturing out in public. And, then there are the effects of COVID-19 on family life as it complicates tending to aged parents or children whose schools closed last spring and may or may not be holding live classes this fall. There is a world of hurt outside our doors, in our communities, across the globe. I know the personal and professional stresses can feel overwhelming.

If the past months have left you feeling dazed and confused, you’re not alone. What lifts my spirits, though, is the brilliant work of the Academy’s leaders and staff as they have pivoted through this pandemic, adjusting quickly to the current environment to create even more value than ever for your AAN membership.

You have been able to take advantage of neuroscience made available online via the AAN’s 2020 Science Highlights so there would be minimal interruption in your awareness and understanding of the great strides made by researchers.

So many of you responded to the deeply discounted education offered by the virtual Sports Concussion Conference and Advanced Practice Providers Neurology Education Series that we exceeded our registration expectations.

Registration is climbing for our virtual Fall Conference, and our move to virtual education makes our programs more accessible to the world than ever.

Members also are taking full advantage of FREE educational opportunities such as the 2019 Annual Meeting On Demand, NeuroBytes, and the Question of the Day mobile app.

As soon as we understood the magnitude of pandemic, we established our COVID-19 Neurology Resource Center at AAN.com, which received more than 136,000 page views between March and July as we curated the latest information from the AAN and around the medical community. In fact, the overall traffic to AAN.com has increased 16 percent compared to last year—despite the cancellation of the Annual Meeting, which is the

12

AANnews • October 2020

biggest driver of web page traffic. Our publications’ websites show higher access as well.

On your behalf, our volunteer members and staff and been working full throttle on regulatory and legislative advocacy issues, particularly surrounding telehealth. The AAN has endorsed numerous bills in Congress specific to improving access to vital telehealth services and expansion of payment for those services. Some of those bills quickly passed in the early stages of the public health emergency and now we are fighting to preserve our gains once the crisis is over. In July, the Academy staged Speak up for Telehealth, an advocacy campaign to bring our members and patients together to promote this position with key decision makers on Capitol Hill.

We also have been engaged with several major payers who are indicating they are extending their coverage of telehealth services. We helped convince CMS to extend the education and

operations testing period for the Appropriate Use Criteria (AUC) program through the end of 2021.

Again, our COVID-19 Resource Center provides a wealth of helpful information on the use of and reimbursement for telehealth services and other practice management topics.

Because of the isolation this disease foisted upon us, from masks and social distancing to quarantines and travel restrictions, we have seen a tremendous increase in conversations within our SynapseSM Online Communities.

Participation in online Section meetings skyrocketed, and 52,000 new social media followers are now following the AAN and publications this year. The AAN truly is your community, helping you stay connected, share your concerns, and find answers in this virtual environment.

Along with working almost daily with a great Board of Directors, committee chairs, and staff whose agility and ingenuity continues to amaze me, I’m also deeply inspired by our rank-and-file members, many of whom I’ve spoken to, out there doing it for themselves—and their patients.

Neurologists who are going above and beyond to treat patients by changing processes, rearranging floor plans, taking on extra duties, even self-producing badly needed PPE. I was elated when I learned the AAN could help you even more by arranging discounted volume pricing on PPE. And I felt humbled by the messages of appreciation from neurologists who were able to benefit from the AAN Neurology COVID-19 Relief Fund to help some of those in dire financial need.

It’s never been clearer to me that the AAN is a true community.

And I urge you to remain a member of this association that is dedicated to meeting your needs throughout your career.

That will be as constant throughout 2021 as it is today. We will continue to bring you the best science and education, whether it is live or virtual. We’ll be the megaphone for your voice in Washington, DC, and advocate for improved patient care around the world to help our growing international membership. We’ll provide the best tools and resources to run your practice or manage your university department. In 2021, we’ll continue to evolve our member benefits—the products, programs, and services that are meaningful to you—and be beside you every step of the way.

Stay healthy. Stay strong. 

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

NEUROLOGY’S MOST PRESTIGIOUS AWARDS AAN Awards recognize the very best, from scientific research to advocacy.

Apply or nominate by October 21, 2020

AAN.com/21Awards

CEO Column

FROM THE CEO Perspectives on Leading the AAN It is an honor and privilege to return to the American Academy of Neurology and to serve as your chief executive officer. I’m thrilled to be reunited with so many of you that I worked with during my prior years with the AAN and look forward to meeting all of you at future meetings when our environment allows. Until then, I think it’s important to share with you some reflections about my leadership in the first six months as your CEO, and my unwavering commitment to our mission and vision.

Who could have expected COVID-19 and the tremendous leadership challenges that neurologists, neurology professionals, and your patients would encounter? You have been tested beyond measure and despite the challenges, I’ve seen you rise to the occasion and continue your pursuit to deliver high quality patient-centered neurologic care. From solo and small practice neurology groups to large multi-specialty groups, academic neurology and research, you have inspired us to persevere and lead on.

Post

We have an incredibly dedicated, collaborative, and trusting relationship between the Board of Directors and staff that has been built on the foundation of our mission and values. During my transition, I worked closely with Dr. James Stevens, AAN President, key New CEO Mary E. Post, MBA, CAE, was introduced to staff last February by outgoing CEO Board members, and the AAN executive team and Catherine M. Rydell, CAE, and AAN President James C. Stevens, MD, FAAN. staff as we addressed the immediate priorities of the organization when the pandemic first ensued. These strong relationships also made it possible for the AAN to quickly issue a position statement on June 4, 2020, condemning racism and the impact inequities have on our members, our patients, and the communities we serve. Together, we ensured that during very chaotic and challenging times, we remained united and focused on the needs of our members and the health and well-being of staff. As a result, we were able to work with confidence and clarity as a new team in an otherwise difficult period.

While I continue to build relationships with the Board of Directors, I am simultaneously focused on supporting the well-being of our staff so they can continue to advance our mission and vision and re-imagine our business strategies. I am regularly meeting with staff in large and

Post shared her excitement about returning to the AAN in a new role.

small groups, speaking about my leadership, and aligning us on our goals and objectives. At a recent meeting, I shared 10 leadership principles that have evolved and guided me over the years, and they encouraged me to share them more broadly with members. I will outline a few of them and over time highlight more about how I am leading the staff.

Know yourself. Self-awareness is key to how you show up as a leader. The better you know yourself and your values, the stronger you will be as a leader of others and the organization. Knowing yourself brings your best self to the table, so pay attention.

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Play the latest Neurology Minute episode.

Believe in positive intent. The more complex we are as an enterprise, the more challenging it can be in our work together. If we start with the premise of believing in positive intent, our best selves will show up in the conversation and our best outcomes will prevail. Even under the most challenging of circumstances, believe in positive intent, and trust we are all doing our best every day.

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Recognize leadership development as an ongoing practice. Leaders grow and develop others as leaders. It is the pinnacle of leadership. I value leadership and commit to continually developing the leader in others.

As leaders, we’re being called upon to operate under extraordinary circumstances. The strength of the leaders we have on our Board of Directors, our committees and subcommittees, and our staff is second to none. They have demonstrated calm deliberation and ingenious creativity as they quickly adapted to crisis and acted boldly to remain indispensable to our members. We’ve turned challenges into opportunity and continue to succeed in ways we hadn’t dreamed. It is the honor of my professional lifetime to serve as your CEO. 

Mary E. Post, MBA, CAE Chief Executive Officer, AAN mpost@aan.com

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AANnews • October 2020 15

Conferences & Community

Deadlines Approaching for Four Unique Leadership Opportunities During these unprecedented times, the AAN is pleased to announce that it will continue to offer its premier leadership development programs over the coming year. AAN members are encouraged to apply or recommend a deserving colleague for one of these all-expenses-paid, transformative programs, designed to equip participants with the leadership skills needed to help advance their careers, the mission of the Academy, and the neurology profession.

No other leadership development programs compare to these unique experiences, which combine training, personalized coaching, mentoring by neurology leaders, and an expansive community of professionals. Past participants have found these programs to be incredibly valuable, and the AAN as an organization has also benefited greatly from these graduates, with many continuing on to work group, committee, and board of director positions.

Practice Leadership / Apply by October 9

Emerging Leaders / Apply by October 9

Designed to develop and hone the unique leadership skills needed by today’s practicing neurologist, with new emphasis on how to adjust one’s practice in the COVID-19 world. Open to US neurologists in solo practice, small group, or in a neurology/ multi-specialty group of 10 or less, participants will develop strategies for business growth, understand the changing regulatory burdens and mitigate their demands on practice, learn strategies to effectively lead staff, and connect with a likeminded support network.

Designed to identify, engage, and mentor talent among early-career members interested in future leadership roles within the AAN and the field of neurology. The multi-month program is open to highly motivated North American member neurologists less than seven years out of residency or training and includes executive leadership education, collaboration with peers on a group project pertinent to AAN strategic plans and priorities, 1:1 leadership coaching, mentoring opportunities, and tools to enhance self-awareness and personal agility, improve communication, lead change, and develop strategic thinking skills.

Visit AAN.com/PLP or contact Nate Kosher at nkosher@aan.com to recommend a colleague or faculty member.

“The [program] was a very unique opportunity for me to collaborate with young physicians around the country, all coming together for a common goal: to grow personally and professionally.

Soileau There were physicians from large clinics, hospitals, solo practices— all of whom brought a different perspective and new skills to the table when discussing common issues we all face. Additionally, we also learned a lot about ourselves and our emotional intelligence, which continues to help me in my day-to-day interactions with patients and my staff. I'm very grateful for the AAN for creating and continuing programs such as the Practice Leadership Program."

—Michael J. Soileau, MD, 2020 Graduate

16

AANnews • October 2020

Visit AAN.com/ELP or contact Sarah Dietman at sdietman@aan.com to recommend a colleague or faculty member.

“We never could have anticipated the trajectory of the upcoming year upon embarking on the Emerging Leaders Program in October 2019. Looking back, it is difficult to think of a year in Kim which clinical leadership worldwide could have been put to a tougher test or one in which the value of the Emerging Leaders Program could have been more apparent.”

—Christine Kim, MD, 2020 Graduate

Transforming Leaders / Apply by October 23 Designed for innovative leaders with aspirations to transform their practice community and the field of neurology. The program is open to US neurologist members seven or more years out of residency. Through personalized coaching, mentorship, and training on agile leadership, communications styles, leading others, and systems and systemic structures, participants will become agents of change with increased confidence to understand, analyze, and solve problems; break through barriers to achieve goals with more clarity, efficiency, and less conflict; work better in teams, leverage the unique strengths of team members, and inspire and motive team members to achieve a common goals; and discover how to get more involved with the AAN. Visit AAN.com/TLP or contact Sarah Dietman at sdietman@aan.com to recommend a colleague or faculty member.

“My experience in the Transforming Leaders Program was truly transformative. It catalyzed many components of my individual project, but also built my skills as a leader. The Husseini program was multi-dimensional, approached leadership from multiple aspects, and made me focus on what's important. I was able use the entire group of very smart people, including my colleagues in the Transforming Leaders Program, the physician leads, my mentor, and my coach, as a sounding board. It was an incredible experience on many levels.”

—Nada El Husseini, MD, 2020 Graduate

Women Leading in Neurology / Apply by October 23 Designed to empower and inspire female AAN member neurologists to tackle gender disparities head-on and advance to top levels of leadership. The program is open to talented and highly motivated mid-career (at least seven years out of residency or training) US-based female neurologists who are committed to the profession of neurology and to providing high-quality patient-centered care. Participants will hone their executive presence to empower and influence others; learn how to negotiate for what they want; manage and lead with confidence; bring awareness to and develop personalized leadership styles through expert-driven conversation; and develop a mastery of leadership at the work group/team and organizational levels.

Visit AAN.com/WLN or contact Nate Kosher at nkosher@aan.com to recommend a colleague or faculty member.

“My participation in the AAN Women Leading in Neurology Program was an invaluable experience! Through the many facets of the program, Women Leading in Neurology helped me Hon know myself more deeply, be able to articulate my strengths and values more clearly, as well as identify and improve areas of needed growth in my personal and professional life. The excellent executive coaching provided me with much needed guidance, assessing my current position and helping me forge a pathway forward into the future. Without question, the professional relationships and friendships developed through the program will continue long after its completion. Even as we were forced into meeting virtually during the pandemic, the program continued to be just as powerful.”

—Sarah J. Hon, DO, FAAN, 2020 Graduate 

AANnews • October 2020 17

In patients with relapsing forms of multiple sclerosis (RMS)

START WITH THE POWER AND EXPERIENCE OF TYSABRI

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

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

1,2

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

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

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

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

MORE THAN

APPROXIMATELY

200,000

15 YEARS OF EXPERIENCE

NEW PATIENTS

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

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

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

PATIENTS TREATED

1 IN 3

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

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

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

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

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

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

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

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

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

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

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

1.

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

2.

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

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

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

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

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

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

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

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

4.

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

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

5.

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

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

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

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

1/10,000

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 2:

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

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

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2

5 <1

9 4

7 3

3 2 1

2 <1 <1

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

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

Table 3:

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

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

TYSABRI n=983 %

Placebo n=431 %

32 10 8 5 2 1

23 8 6 4 <1 <1

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

6 1

4 0

2

<1

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

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

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

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Blood disorders: hemolytic anemia, 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

Conferences & Community

The AAN in the Media Spotlight This summer, the AAN and the journal Neurology ® received great media coverage.

Studies that suggest things such as making simple changes in your diet, taking a vitamin supplement, or flossing your teeth to prevent neurologic problems down the road got traction in the news. One of those relatable Neurology studies was on older women and whether eating enough fish with omega-3 fatty acids counteracts the effects of air pollution on the brain; it was covered by the New York Times, the Daily Mail, US News & World Report, CNN, and at least a dozen TV stations. Another Neurology study that suggests simple vitamin D and calcium supplements may prevent the recurrence of vertigo was covered by the Daily Mail, Health Day, and more than 50 TV stations. As for the dental floss? A study in Neurology that made a connection between gum disease and dementia connected with readers from the New York Times and CNN.

We are all looking for ways to be more focused when working from home, and AAN President Elect Orly Avitzur, MD, MBA, FAAN, gave the Wall Street Journal her top tips for increasing your productivity. Many people are trying to get more exercise during the pandemic, and biking is popular. David W. Dodick, MD, FAAN, offered some timely advice about protecting your brain with a bike helmet, and what to look for when buying one, in a Forbes article.

Finally, John C. Morris, MD, FAAN, was interviewed by the New York Times about a Neurology study showing rates of dementia falling about 10 percent per decade in the US and Europe. 

Upcoming Virtual Fall Conference Program Highlights Practice Management talks:

Coding Updates: E/M Mastering the Regulatory and Legislative Landscape in 2021 Payer Contract Analysis and Negotiating Strategies Revenue Cycle Optimization Building Service Lines in Your Practice Telemedicine: Taking Virtual Care to the Next Level Recruitment, Hiring, and Retention: Developing Your Talent Management Program

Don’t miss these highly popular sessions—previously offered during the AAN Annual Meetings—now in a new virtual format: Beyond the Bedside session focusing on the business side of a practice Curbside Consults featuring experts discussing unique cases and providing guidance on diagnosis and treatments in neuro-oncology and neuroimaging

Continued from cover

Tips for the virtual Neuro Exam

Virtual Exhibit Hall

Entertaining educational offerings such as the Neuro Story Slam

“How to” lectures on topics such as billing for a telehealth visit or how to combat burnout in the workplace

Continuum® Test Your Knowledge: A Multiple-Choice Question Review I and II with topics on Neuromuscular Disease and Autoimmune Neurology Industry Pipeline talks Special networking opportunities for special interest groups, a NeuroJeopardy social event, and a musical act

Scientific programs including Controversies in Neurology Plenary Session and Neuroscience in the Clinic Sessions Social events such as a musical act and neurology-related trivia 

Education & Research

Application for Accreditation of Subspecialty Fellowship Programs Due by December 1

Applications for subspecialty fellowship programs seeking United Council for Neurologic Subspecialties (UCNS) accreditation are due by December 1. Accreditation is a measure of training program excellence and UCNS-accredited programs demonstrate that they meet the standards of graduate medical education excellence set by both the UCNS and the subspecialty experts of each of the UCNS-recognized subspecialties. The peer-reviewed accreditation process is overseen by the Accreditation Council, a standing committee reporting to the UCNS Board of Directors. Visit UCNS.org/Accreditation to learn more and to apply. 

October 21 Application Deadline Approaching for 2021 AAN Awards No matter where you are in your career, there is an AAN award designed to recognize everything from scientific research to advocacy, safety, and quality. Be sure to visit AAN.com/21Awards

by October 21 to apply or nominate a colleague for one of the many available awards offering opportunities to be recognized and honored during 2021 AAN Annual Meeting; to receive travel stipends, if needed; or to present your work to your colleagues. Some award winners even get their work picked up by major media outlets! 

Accreditation-only Option Now Available for Subspecialty Training Programs Emerging neurologic subspecialties now have the option to apply for an accreditation-only option when seeking subspecialty recognition and accreditation for their subspecialty training programs through the United Council for Neurologic Subspecialties (UCNS).

The UCNS accredits neurologic subspecialty training programs that meet the educational standards established by the subspecialty and awards certification to physicians who demonstrate their knowledge in one or more of the UCNS neurologic subspecialty areas. The accreditationonly option provides an opportunity for subspecialties to offer accreditation for fellowship training programs while evaluating the interest and sustainability of providing certification for the subspecialty. Subspecialties applying for recognition may now opt for UCNS accreditation and certification or for accreditation-only for the subspecialty.

“The UCNS organizational vision is to help small neurologic subspecialties

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AANnews • October 2020

develop credibility and grow,” said UCNS Board Chair Paul G. Fisher, MD. “The UCNS Board recognizes that there are fellowship training programs developing for many emerging subspecialties, but it may be too early for them to support a certification process. Offering an accreditation-only option aligns with the UCNS mission and vision and provides an opportunity for neurologic subspecialties to have a process for development and oversight of their training program standards that they would not otherwise have during their early growth. Subspecialties applying for accreditation-only may request the implementation of certification at a later date when sustainable growth and interest is demonstrated.”

The peer-reviewed accreditation process is overseen by the Fisher Accreditation Council, a standing committee reporting to the UCNS Board of Directors.

There are currently 206 UCNS accredited fellowship training programs across eight neurologic subspecialties.

Neurologic subspecialties interested in applying for UCNS recognition can learn more at UCNS.org/ SubspecialtyRecognition. 

Latest Continuum Examines Peripheral Nerve and Motor Neuron Disorders Those looking for the latest information on peripheral nerve and motor neuron disorders should look to the latest issue of Continuum: Lifelong Learning in Neurology ®.

According to the issue’s guest editor, A. Gordon Smith, MD, FAAN, “The breadth and innovation of new therapies for peripheral nerve disorders is breathtaking, ranging from molecular therapies for inherited disorders to innovative immunotherapies and promising approaches to treating ALS. This issue also includes important information about how we can judge the value that new, and often expensive, treatments bring to patients and to society.”

Smith

The lineup of excellent articles will offer some surprising new information to readers, according to Smith. “While readers will learn about many exciting new technological and therapeutic advances, I think most will be surprised to recognize that the best patient-centered care for those with peripheral nerve disorders is still founded in an excellent history and physical examination, and that consideration of testing and treatment value is essential to ensuring all patients have access to these innovations.”

The robust issue’s topics include: A Structured Approach to the Diagnosis of Peripheral Nervous System Disorders Zachary N. London, MD, FAAN Diabetes and Metabolic Disorders and the Peripheral Nervous System Christopher H. Gibbons, MD, MMSc, FAAN

Rising Drug Costs for Neurologic Diseases Jason L. Crowell, MD; Ted M. Burns, MD Test Utilization and Value in Peripheral Neuropathies Brian C. Callaghan, MD, MS, FAAN

Guillain-Barré Syndrome Kazim A. Sheikh, MBBS

Added Smith, “I routinely use Continuum at the point of care.

Neurologists will find lots of clinically relevant information in this issue that will facilitate accurate diagnosis and assist in selecting the best treatment approach for patients they encounter in day-to-day practice.”

Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its Variants Kelly Gwathmey, MD

As always, this 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.

Charcot-Marie-Tooth Disease and Hereditary Neuropathies Christopher J. Klein, MD, FAAN

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. 

Peripheral Neuropathies Associated with Vasculitis and Autoimmune Connective Tissue Disease Chafic Karam, MD Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and Medications Nathan P. Staff, MD, PhD, FAAN Management of Neuropathic Pain in Polyneuropathy Amanda C. Peltier, MD, MS; Derek Wood, MD Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases Colin Quinn, MD; Lauren Elman, MD Spinal Muscular Atrophy Jessica Rose Nance, MD Peripheral Neuropathies Associated with Monoclonal Gammopathies Including Myeloma Elie Naddaf, MD; Michelle L. Mauermann, MD, FAAN Test Utilization and Value in Peripheral Neuropathies Brian C. Callaghan, MD, MS, FAAN

AANnews • October 2020 27

Policy & Guidelines

Capitol Hill Report: Election Special Edition 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.

This is a special report for AANnews on the upcoming elections.

AAN Member Runs for Congress with Support from BrainPAC

we do agree. I strongly felt we needed more moderate candidates to run to bring us all together and bring unity back to America.”

BrainPAC is the only federal political action committee that specifically represents neurology and allows the AAN to increase the influence and profile of neurology on Owensby Capitol Hill. Along with supporting certain congressional incumbents who have championed neurology issues, BrainPAC also identifies a select number of non-incumbent, or first-time, candidates to support in the federal election. For these candidates, an expertise in health care is essential, meaning most supported by BrainPAC are physicians, dentists, other health care professionals, or those with close ties with an AAN member. During this election cycle, BrainPAC has contributed to five non-incumbents: four physicians and AAN member Alexandra Owensby, DNP.

Did you have advocacy experience before deciding to run?

Owensby is making her first attempt at public office, running for the House of Representatives as the Democratic nominee for Kentucky’s 4th District. It’s not often an AAN member runs for office, and Owensby was kind enough to take some time from campaigning to share her experiences in politics during a pandemic.

What compelled you to run?

“I think there were several things which ultimately inspired me to run. First and foremost, witnessing day in and day out our broken health care system. Every day I talk to my patients, it is clear to me that we need to do something to fix the system we have. We need a system where people can afford their medications, where people can afford to get small health problems addressed before they become big health problems, and where people have access to medical care regardless of their employment status. The second major inspiration for me was seeing our broken political system. While members of the House and Senate are meant to be our representatives, most don't have lives that represent the vast majority of Americans. Many elected officials have no idea what it is like to struggle. Many have no idea the challenges faced every day by working- and middle-class families. I had this nagging feeling in my heart that we had to do better, we need representatives that understand these issues if we are ever going to overcome them. The final inspiration for me to run is the divisive political climate in which we are entrenched. I have Republican friends and Democratic friends and we both agree on 90 percent of the issues, but the current political environment is such that we focus on our differences instead of the areas where

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AANnews • October 2020

“No formal advocacy work. I had attended a few protests locally for things I disagreed with, but never anything on a formal level.”

What neurology issues are you championing?

“I will be a strong partner in working to ensure research funding for neurological diseases is never cut and is increased as appropriate. I will, also, be a strong partner in working to develop a health care system that is affordable and accessible for all Americans. We need to build a system that is not tied to employment and one that focuses on preventing problems rather than curing them. A third issue I will address is more consistent reimbursement for telemedicine services. Between the COVID-19 crisis and rural hospitals shutting down at alarming numbers, we are seeing the benefits of telemedicine services now more than ever. We need to ensure these services are being fairly reimbursed.”

Do you have any mentors who are helping you?

“I do not have any mentors specifically working on my campaign with me, but I do have a number of very strong, amazing women in my community who give me a lot of moral and emotional support throughout the process! I have been fortunate enough to have connected with several other women (and men) who are running for Congress and we have formed our own support group where we trade ideas and commiserate when needed!”

How have you had to adapt your campaign due to COVID? “COVID-19 has been beyond interesting to adapt to in the campaign! The first half of my campaign was focused primarily on attending every community event possible and was a lot of shaking hands. The second part of my campaign has been focused on Zoom and learning how to shoot decent videos of myself and how to get the lighting right. COVID-19 has helped in some ways, as my district is very large and now I can do multiple meetings a night that would usually take two to three hours each of drive-time in between. However, Zoom events are not as well attended and in-person fundraising is no longer possible. We have also, like the rest of the world, had to learn how to be very innovative! A traditional campaign would have large events with speeches, people knocking doors to talk to voters, etc. All of those avenues are gone. We have had to come up with new ways to get

my name and message out to voters, which has been interesting.

Kentucky has also never allowed mail in voting or early voting prior to COVID-19, so my campaign has had to learn how to focus on a month of voting instead of one set day.”

What’s the most surprising or strenuous part of campaigning?

“The time constraints are for sure difficult. As a full-time single mom to two children, who was also working full time until recently, the time constraints are always the hardest part. I tend to never look more than one day ahead on my schedule because it would just be too overwhelming to think of everything I need to do between now and the election! But, between taking things one day at a time and my amazing support network, it all becomes doable in the end. I have also had to learn to ask for help, which is something that is very hard for me to do! However, people have been amazing about stepping in to bring the kids and me meals, helping me drive my signs all over the district, etc. It has really made me realize how strong my community is and how much we can get done together.”

What is the most rewarding part?

“The most rewarding part is the friends I have made along the way and knowing that I stepped up to the plate in a time where it really mattered. I have had a number of men and women come up to me and tell me they had always thought about running for office but were intimidated by the process. They say after seeing me take on Congress though, they realized they could handle running for school board or whatever office they had been considering.

Regardless of whether I win or lose in November, if I have inspired others to step up and get involved in our government, then I will have accomplished something incredible.”

Republican Physician Aims for Senate Seat BrainPAC is bipartisan in its support, and one of the Republican lawmakers benefiting is Roger Marshall, MD. He’s a Kansas ob/gyn currently serving in the House of Representatives from the 1st District, and he’s running for an open Senate seat. While in the House, Marshall has had numerous interactions with the AAN and our advocacy team. He is a lead sponsor on legislation to address the burdens associated with prior authorization, the Improving Seniors’ Timely Access to Care Act (H.R. 3107), which was a Neurology on the Hill priority issue in 2020. He won a competitive primary for this Senate seat against the former Kansas secretary of state. In a state that favors Republican, he will face a Democratic candidate in the general election who is also a physician, Barbara Bollier, MD. BrainPAC has supported

During a recent fundraising visit to Texas, Marshall visited staff at Texas Neurology, PA. (From left) David A. Evans, MBA; Waleed Hamed El-Feky, MD; Marshall; and Daragh Heitzman, MD, FAAN.

Marshall since 2018. If he joins the US Senate, he’ll be a new senator who is a proven champion for neurology issues and knows the AAN very well.

How BrainPAC Supports Neurology-friendly Candidates for Congress BrainPAC provides the AAN with direct access to congressional candidates, members of Congress, and their staff during special events hosted specifically to raise funds for their election.

Through these events, the AAN can build relationships with key decision makers that prove invaluable year after year. Typically, during each two-year election cycle BrainPAC contributes nearly $500,000 to more than 100 congressional candidates.

BrainPAC doesn’t contribute to presidential candidates. Donations to BrainPAC come from US members and staff of the AAN as permissible by law.

The AAN’s BrainPAC Executive Committee determines the criteria for which candidates receive BrainPAC support each year.

An objective scoring system is used to guide BrainPAC’s political contributions to ensure they are strategic and transparent. This scoring system weighs several factors to determine whether a member of Congress has a track record of supporting AAN priorities and is in a position to influence the health care debate on the Hill.

To learn more about BrainPAC, visit BrainPAC.org. 

AANnews • October 2020 29

FOR PATIENTS WITH RELAPSING FORMS OF MS

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

Indication

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

Important Safety Information

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

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

CONTRAINDICATIONS

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

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

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

© 2020 Biogen. All rights reserved. 08/20 VUM-US-0458

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

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

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

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

Visit www.vumerityhcp.com

RRMS=relapsing-remitting multiple sclerosis.

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

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

Pharma Ad

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

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

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

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

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

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

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

VUMERITY® (diroximel fumarate) delayed-release capsules, for oral use of the brain caused by the JC virus (JCV) that typically only occurs Brief Summary of full Prescribing Information in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who 1. INDICATIONS AND USAGE received dimethyl fumarate for 4 years while enrolled in a clinical trial.

VUMERITY is indicated for the treatment of relapsing forms of multiple During the clinical trial, the patient experienced prolonged lymphopenia sclerosis (MS), to include clinically isolated syndrome, relapsing- (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years) while remitting disease, and active secondary progressive disease, in adults. taking dimethyl fumarate [see Warnings and Precautions (5.4)]. The patient had no other identified systemic medical conditions resulting 2. DOSAGE AND ADMINISTRATION in compromised immune system function and had not previously 2.1. Blood Tests Prior to Initiation of VUMERITY been treated with natalizumab, which has a known association with Obtain the following prior to treatment with VUMERITY: PML. The patient was also not taking any immunosuppressive or • A complete blood cell count (CBC), including lymphocyte count immunomodulatory medications concomitantly. [see Warnings and Precautions (5.4)].

PML has occurred in patients taking dimethyl fumarate in the • Serum aminotransferase, alkaline phosphatase, and total bilirubin postmarketing setting in the presence of lymphopenia (<0.9 × 109/L). levels [see Warnings and Precautions (5.5)].

While the role of lymphopenia in these cases is uncertain, the PML 2.2. Dosing Information The starting dosage for VUMERITY is 231 mg twice a day orally. After 7 days, the dosage should be increased to the maintenance dosage of 462 mg (administered as two 231 mg capsules) twice a day orally.

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

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

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

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

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

cases have occurred predominantly in patients with lymphocyte counts <0.8×109/L persisting for more than 6 months.

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

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

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

2.4. Blood Tests to Assess Safety After Initiation of VUMERITY Obtain a complete blood cell count (CBC), including lymphocyte count, 6 months after initiation of VUMERITY and then every 6 to 12 months 5.3. Herpes Zoster and Other Serious Opportunistic Infections thereafter, as clinically indicated [see Warnings and Precautions (5.4)]. Serious cases of herpes zoster have occurred in patients treated Obtain serum aminotransferase, alkaline phosphatase, and total with dimethyl fumarate (which has the same active metabolite as bilirubin levels during treatment with VUMERITY, as clinically indicated VUMERITY) including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster [see Warnings and Precautions (5.5)]. meningomyelitis. These events may occur at any time during treatment.

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

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

West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium 3. DOSAGE FORMS AND STRENGTHS VUMERITY is available as hard, delayed-release capsules containing tuberculosis) infections. These infections have been reported in 231 mg of diroximel fumarate. The capsules have a white cap and a patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, white body, printed with “DRF 231 mg” in black ink on the body. meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and 4. CONTRAINDICATIONS ear. Patients with symptoms and signs consistent with any of these VUMERITY is contraindicated in patients infections should undergo prompt diagnostic evaluation and receive • With known hypersensitivity to diroximel fumarate, dimethyl appropriate treatment. fumarate, or to any of the excipients of VUMERITY. Reactions Consider withholding VUMERITY treatment in patients with herpes may include anaphylaxis and angioedema [see Warnings and zoster or other serious infections until the infection has resolved [see Precautions (5.1)].

Adverse Reactions (6.2)].

• Taking dimethyl fumarate [see Drug Interactions (7.1)] 5.4. Lymphopenia 5. WARNINGS AND PRECAUTIONS VUMERITY may decrease lymphocyte counts. In the MS placebo5.1. Anaphylaxis and Angioedema controlled trials with dimethyl fumarate (which has the same active VUMERITY can cause anaphylaxis and angioedema after the first metabolite as VUMERITY), mean lymphocyte counts decreased by dose or at any time during treatment. Signs and symptoms in patients approximately 30% during the first year of treatment with dimethyl taking dimethyl fumarate (which has the same active metabolite as fumarate and then remained stable. Four weeks after stopping dimethyl VUMERITY) have included difficulty breathing, urticaria, and swelling fumarate, mean lymphocyte counts increased but did not return to of the throat and tongue. Patients should be instructed to discontinue baseline. Six percent (6%) of dimethyl fumarate patients and <1% of VUMERITY and seek immediate medical care should they experience placebo patients experienced lymphocyte counts <0.5 × 109/L (lower signs and symptoms of anaphylaxis or angioedema. limit of normal 0.91 × 109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with 5.2. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred in dimethyl fumarate or placebo, respectively. There was no increased infections observed in patients with lymphocyte patients with MS treated with dimethyl fumarate (which has the same incidence of serious 9 9 active metabolite as VUMERITY). PML is an opportunistic viral infection counts <0.8 × 10 /L or ≤0.5 × 10 /L in controlled trials, although one

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

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

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

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

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

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

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

Adverse Reactions

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

Placebo (N=771)%

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

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

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

• Herpes Zoster and Other Serious Opportunistic Infections [see Adverse Reactions in Clinical Studies with VUMERITY Warnings and Precautions (5.3)].

In clinical studies assessing safety in patients with RRMS, approximately • Lymphopenia [see Warnings and Precautions (5.4)].

700 patients were treated with VUMERITY and approximately • Liver Injury [see Warnings and Precautions (5.5)].

490 patients received more than 1 year of treatment with VUMERITY. • Flushing [see Warnings and Precautions (5.6)].

The adverse reaction profile of VUMERITY was consistent 6.1. Clinical Trials Experience with the experience in the placebo-controlled clinical trials with Because clinical trials are conducted under widely varying conditions, dimethyl fumarate. adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 6.2. Postmarketing Experience The following adverse reaction has been identified during post approval may not reflect the rates observed in clinical practice.

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

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

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

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

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

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

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

Inform patients to swallow VUMERITY capsules whole and intact.

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

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

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

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

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

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

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

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

Pregnancy 8.4. Pediatric Use Safety and effectiveness in pediatric patients have not been Instruct patients that if they are pregnant or plan to become pregnant while taking VUMERITY they should inform their healthcare provider established. [see Use in Specific Populations (8.1)].

8.5. Geriatric Use Clinical studies of dimethyl fumarate and VUMERITY did not include 54499-02 sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Manufactured for: Biogen Inc. 8.6. Renal Impairment No dosage adjustment is necessary in patients with mild renal Cambridge, MA 02142 impairment. Because of an increase in the exposure of a major metabolite [2-hydroxyethyl succinimide (HES)], use of VUMERITY is VUMERITY is a registered trademark of Biogen. not recommended in patients with moderate or severe renal impairment © Biogen 2019 - 2020 [see Clinical Pharmacology (12.3)].

Tools & Resources

Axon Registry Participants Share How They Benefit

reviewing MIPS results, NRC Health Patient Experience Survey data, and talking with staff and providers about processes to improve. I then develop a yearly Quality Improvement Plan which is presented to the board of directors at their yearly retreat. Once approved, I share the QI Plan with leaders, providers, and staff.”

Vinson. Since telemedicine is now the main platform for patient visits, “our practice reviewed data specifications to see if telemedicine codes were included in measures and checked in with QPP to see if telemedicine visits would count towards the denominator for MIPS measures.”

At the Noran Neurological Clinic, Like many other health care Sara Valentine is director of health organizations, the Minneapolis Clinic of information services. She shared, “The Neurology had to adjust to the COVID-19 data in the Axon Registry has helped us pandemic. One of those changes has successfully submit for MIPS the past been to use telemedicine at a higher several years and each year we have rate. “MIPS training was redesigned been scored in the top/bonus category.” for providers so they could facilitate The other helpful benefit is the ability 20 CHP Advocacy Awareness Ad: AANnews, NJ, NCP: Half Page Horizontal via Resolution Zoom rather than in person,” said NeurologytoJournal, have registry participation assist in USAGE: High PDF to be placed in AANnews, or Neurology Clinical Practice

Continued from cover

completing their requirement for part IV of continuing certification established by the American Board of Psychiatry and Neurology. “The part IV continuing certification requirement has been a significant benefit to the providers,” said Valentine.

The Axon Registry is a valuable tool that enables neurology practices to identify and improve gaps in the quality of neurologic care, demonstrate their value to payers, and compare their performance to neurologists nationwide.

If you’re interested in learning how the Axon Registry—free only to AAN US members—can help your clinic or private practice, visit AAN.com/axon or email registry@aan.com. 

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BE INFORMED. GET ENGAGED. Read Capitol Hill Report

From the halls of Congress to the offices of regulatory agencies, AAN members and advocacy staff are working tirelessly to represent the needs of you and your patients. Stay up to date with Capitol Hill Report at AAN.com/view/HillReport. or on Twitter at #AANadvocacy.

Tools & Resources

Get Great Tips from These Practice Management Webinars The previously postponed April and June AAN Practice Management Webinars are now available, and the August and October webinars will be available on October 13. Visit AAN.com/pmw20 for more details on the webinars below. 

APRIL

JUNE

AUGUST

OCTOBER

Patient Engagement that Works for Your Practice

Making Reimbursement Work in Your Practice

Leading Your Practice to Excellence

Practice Sustainability Through Proper Financial Management

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

36

AANnews • October 2020

AAN.com/FAAN

Comment Invited on Two Draft Guidelines, Quality Measures The AAN is inviting public comment over the coming weeks on two draft guidelines and one quality measurement set. To read the full guidelines and share your insights, visit AAN.com/view/PublicComment.

Treatment of Parkinson Disease Guideline Comments due by October 28, 2020 This practice guideline update includes conclusions and recommendations that address: The efficacy and adverse effects of levodopa, dopamine agonists, and MAO-B inhibitors for treating motor symptoms of early Parkinson disease.

Clinical considerations in deciding whether to initiate levodopa, dopamine agonists, or MAO-B inhibitors in patients with early Parkinson disease.

The overall messages of this practice guideline update are: The best treatment for motor symptoms in early Parkinson disease is levodopa.

Some patients are afraid to start levodopa due to potential adverse effects; this guideline may help reassure these patients that levodopa is effective and causes fewer adverse effects than alternative medications.

Dopamine agonists must be prescribed safely; clinicians should inform patients and caregivers of the potential side effects and recommend tapering or discontinuing dopamine agonists if patients experience disabling medication-related adverse effects.

This practice guideline update addresses the following gaps in care: There is currently variation in clinicians’ prescribing practices for treating motor symptoms in early Parkinson disease. This guideline provides direction to clinicians and patients on the effectiveness and possible adverse effects of levodopa, dopamine agonists, and MAO-B inhibitors.

Treatment of Painful Diabetic Polyneuropathy Guideline Comments due by November 5, 2020 This practice guideline update includes conclusions and recommendations that address: Many new studies published since the 2011 guideline of the same medicines covered in the 2011 guideline, including new studies on sodium channel blockers that changed recommendations Evolving literature, outside of opioids, that led to recommendations The recognition now among the medical community that the risks of the use of opioids for therapy outweigh the benefits The overall messages of this practice guideline update are:

Think about treatment in terms of classes of medication.

Switch medication classes; if one class is not working, try another class. Don’t try another medication in the same class.

Think about use for individual patients in terms of patient preference, cost, comorbidities, effect sizes, side effect profiles.

This practice guideline update addresses the following gaps in care: Gaps in the prescription of efficacious medications other than gabapentin and pregabalin, which are prescribed a lot.

Gaps in discussion of nerve pain between clinicians and patients Gaps in the knowledge shared between neurologists and primary care physicians, who see patients with PDN much more often than neurologists, about current treatments and management strategies for this condition and understanding of the need to communicate PDN issues with the patients’ neurologists Gaps in patient adherence to treatment. Evidence shows that often patients give up on medications too early before moving on to opioids Gaps in individualized treatment plans. Medications have small effect sizes and potential for side effects. Frequent follow-up is needed to find the medication that works best for the patient

Polyneuropathy Quality Measurement Set Comments due by November 5, 2020 As part of the Practice Guideline Update: Treatment of Painful Diabetic Polyneuropathy, the AAN conducted a joint quality measure development project to develop quality metrics from updated recommendations.

This quality measurement set includes three measures: Avoidance of Opioid Medications for Patients with Painful Diabetic Neuropathy Pain Assessment and Follow-up for Patients with Diabetic Neuropathy Reduction of Pain for Patients with Polyneuropathy The intent of this quality measurement set is to drive practice improvement for patients with polyneuropathy. Measures address treatment team processes, intermediate outcomes, and outcomes for patients with polyneuropathy. 

Don’t use opioids. This includes SNRI/opioid medications such as tramadol and tapentadol.

AANnews • October 2020 37

Tools & Resources

Stumped? Send Your Practice-related Questions to practice @aan.com The practice@aan.com email inbox is an efficient way to reach staff and member expertise on practice-related topics such as payers, MIPS/MACRA, coding, and practice management. Staff experts respond within one business day and can seek the assistance of the Practice Support Network, a group of 29 practicing neurologists and graduates of the AAN’s Practice Leadership Program, for real-world expertise. Below are some common recent questions.

PRACTICE MANAGEMENT

CODING

Q: Do I need to consult appropriate use criteria (AUC) when ordering an advanced image?

Q. When reporting the professional component of a long-term EEG study, if a download of the VEEG data is received every 24 hours instead of a single download at the end of an ambulatory study, can we bill code 95718 or 95720?

A: Y es. The Protecting Access to Medicare Act will require physicians ordering advanced imaging to consult AUC via a qualified clinical decision support mechanism (CDSM). The program’s education and operational testing period has been extended through 2021, and the full program is expected to go into effect January 1, 2022.

The ordering physician will be required to provide the appropriate G-code indicating the CDSM consulted, AUC adherence, and their NPI number when ordering an advanced image. Claims submitted after the education and operational testing period may be denied, and the top five percent of outlying ordering physicians may be required to submit prior authorizations when ordering images.

A: T his is a common question and the answer is no. As stated in the March 2020 issue of the AMA CPT® Assistant, “Codes 95717–95720 (long-term EEG monitoring services) are meant to be reported when the physician has access to the EEG data throughout the duration of the recording (intended to guide interventions or alterations in care during the recording period) and generates daily report for each 24-hour segment of the recording with a summary report at the conclusion of the multiday studies. If these requirements are not met, the correct code to report for the professional component would be chosen from the EEG family of codes 95721–95726.” Learn more at AAN.com/CPT.

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QUALITY PAYMENT PROGRAM Q: I can’t keep track of all of the QPP deadlines!

What should I be paying attention to right now?

A: We know there is a lot to keep track of when it comes to QPP. Because the QPP has a two-year lag where payment in the current year is determined by the performance year two years prior, practices are balancing three years of QPP at any given time; 1) understanding their payments this year based on performance year two years ago; 2) reporting for the current MIPS year; 3) preparing for changes in the upcoming MIPS year. For this year, that means understanding 2018 performance/2020 payments, reporting for 2020, and preparing for QPP changes in 2021.

Currently, neurologists and neurology APPs should be reporting in the 2020 MIPS performance year. For practices that cannot report due to COVID-19 or other factors, CMS has opened its Extreme and Uncontrollable Circumstances Exception application. Practices can apply to waive any/all MIPS components through December 31, 2020, and can access the application at qpp.cms.gov/mips/exception-applications.

Additionally, performance feedback and final scores from the 2019 reporting year, which will affect 2021 payments, is now available. Practices can log in at qpp.cms.gov/login and review their performance and request a targeted review if they believe there has been an error in their 2019 performance score.

Practices interested in a targeted review must submit a request

by October 5, 2020. Learn more at AAN.com/view/QPP. 

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NEUROLOGY COMPENSATION AND PRODUCTIVITY SURVEY DATA AVAILABLE! Compare. Act. Improve.

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OUR UNDERSTANDING OF ALZHEIMERâ&#x20AC;&#x2122;S DISEASE IS EVOLVING. SO SHOULD THE WAY WE MANAGE IT.

IF ACCUMULATING AMYLOID BETA IS PART OF HIS PAST, DETECTING MILD COGNITIVE IMPAIRMENT MAY BE YOUR BEST CHANCE TO CHANGE HIS FUTURE.1

A

lzheimer’s disease (AD) is a slow, progressive disease. Amyloid beta can accumulate for decades before there are any symptoms. But after symptoms appear, a patient has, on average, 2 to 6 years before dementia sets in.2-4

This symptomatic predementia is called mild cognitive impairment (MCI) due to AD, and it is the earliest opportunity to begin managing the disease. It is possible to mistake MCI due to AD for normal aging or other forms of MCI with different causes. But advancements in biomarker testing mean it is now possible to confirm whether AD pathology is the underlying driver.1,4-7

Some may believe the lack of treatments indicated for the MCI due to AD stage means there is no benefit to early detection. But progress surrounding our understanding of the disease is a cause for optimism.

New studies show that diagnosis with biomarker confirmation may lead to more optimal management, including nonpharmaceutical interventions.1,8,9 As our understanding of AD continues to evolve, it’s important that our approach to managing it does as well.

And that change can begin by taking steps to detect it earlier.

MCI due to AD is the first symptomatic stage of Alzheimer’s disease.4 Preclinical AD

MCI DUE TO AD

Mild AD Dementia

Moderate AD Dementia

Severe AD Dementia

Mild cognitive symptoms appear, but they do not yet interfere with daily activities.

There is more to know about MCI due to AD. See what early detection can mean for your patients at identifyalz.com.

References: 1. Anderson ND. State of the science on mild cognitive impairment (MCI). CNS Spectr. 2019;24(1):78-87. 2. Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers. 2015;1:15056. doi:10.1038/nrdp.2015.56.

3. Wilson RS, Leurgans SE, Boyle PA, Bennett DA. Cognitive decline in prodromal Alzheimer disease and mild cognitive impairment. Arch Neurol. 2011;68(3):351-356. 4. Alzheimer’s Association. Alzheimer’s Association Report: 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16(3):391-460. 5. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.

Alzheimers Dement. 2011;7(3):270-279. 6. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):257-262.

7. Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562. 8. Rabinovici GD, Gatsonis C, Apgar C, et al. Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA. 2019;321(13):1286-1294.

9. Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-2263.

©2020 Biogen. All rights reserved. 07/20 ALZ-US-0367

Tools & Resources

Frampton Comes Alive in Latest Brain & Life Rock musician Peter Frampton was diagnosed with inclusion body myositis in 2015, after tripping and falling a few times and losing 10 pounds. Since his diagnosis, he has embraced exercise and partnered with Johns Hopkins University to raise awareness and funds. He is proud to be a spokesperson for inclusion body myositis and invited people with the condition backstage after his farewell tour in 2019. He has since published a memoir and was enrolled in a clinical trial of a diabetes drug before the pandemic. Frampton shares how he has coped with the pandemic, including home exercise and online classes, as well as his experiences with doctors and physical therapy via telehealth.

affects health and provides tips for overcoming it, such as staying active, finding meaningful activities, keeping connected, etc.

In other departments, stories explore the implications of COVID-19 on smokers and vapers, how caregivers are coping during this unusual time, and how wearing a mask can affect transmission of the coronavirus.

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Alzheimer’s Promising Research Offers Hope Loneliness How to Ease Social Isolation During the Pandemic Caregiving Lessons Learned from COVID-19

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Frampton says pla ying guitar keeps strong after a dia him gnosis of inclus ion body myositis

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American Brain Foundation

Personal Experience Leads McCain to Foundation Board of Directors Cindy McCain has endured two of most painful diseases of the brain: personally, as a longtime migraine sufferer, and as a caregiver to her late husband, Arizona senator and presidential candidate John McCain, who succumbed to the effects of glioblastoma in August 2018. After she was introduced to the work of the American Brain Foundation (ABF), she became an ardent supporter and, in January 2020, joined its Board of Directors. McCain is experienced in taking on high-profile leadership roles, as she serves as chair of the McCain Institute for International Leadership and its Human Trafficking Advisory Council that strives to end labor and sex trafficking.

McCain shared her personal experiences and how brain research became such an impassioned part of her work.

What inspired you to get involved in the American Brain Foundation?

“Throughout my life I have suffered migraines. I became involved in the community in general just to help facilitate a cure or something that could relieve all of us that get the same kinds of migraine headaches. There's no cure, no possibility of leading a normal life with that. That is what initially drew me to the cause, and of course since my husband's glioblastoma and subsequent death, the ABF became very important to me.

Glioblastoma is a cunning monster, there is no real cure as with many cancers, but there's also not much in the way of being able to treat it. So, those of us that wind up with glioblastoma or caring for someone with glioblastoma learn a great deal about not only the scientific portion of glioblastoma and not only the effect it has on the patient but also on the family. It's very important to me that anything dealing with glio is something that I am interested in and want to be a part of, and the ABF does a great job of highlighting the issue.”

The issue of glioblastoma, what occurred during and after?

“When John was diagnosed, I had heard of brain cancer in general terms, but I had never heard the word glioblastoma.

It opened up a world to my husband and to my family, it was almost too large to grasp. That something that small could be that devastating to one's body. I did hear from a lot of people that were suffering, had suffered, or had lost someone to glioblastoma. I still do. I have heard from survivors, which is wonderful, and from others that have lost someone that they love. It’s never easy for anyone. Glioblastoma is a real challenge

to the medical community because it's so cunning. Even the attempts to relieve it and the McCain radiation and the chemo and like most cancers you are never quite sure you got it all, and in the case of glio, it comes back with a vengeance.”

Have you shared your debilitating issue of migraines publicly?

“When I was first diagnosed with migraines, those were the days that the doctors would tell you it’s stress, go home and have a drink or go take a nap and as any migraine sufferer knows, that doesn't fix it. Adding a chemical to your body like alcohol can only exacerbate the migraine. I'm very hopeful and very excited about the new process and medications that are coming out. I speak to my neurologist quite often about this and am excited. Hopefully, we can cure it or at least tamp it down so sufferers can live with it. As anyone knows who suffers from migraines, it's like having an ax in your forehead. But I am really encouraged by the progress that is being made.”

How did your family deal with your migraines?

“My husband was very kind to me about it, I am not sure he completely understood it for a long time, but he was very understanding and kind and felt terrible for me. There wasn't much he could do except help with the kids and leave me in a dark room. The kids didn't always understand. All of the sudden mommy is supposed to see you play the clarinet in the music festival, but she can't go because she is flat with a migraine.

Stuff like that made me feel really guilty, the guilt involved in it.

You try your best and muddle through it when you can, but I felt

“When John was diagnosed, I had heard of brain cancer in general terms, but I had never heard the word glioblastoma.

It opened up a world to my husband and to my family, it was almost too large to grasp. That something that small could be that devastating to one's body.”

44

AANnews • October 2020

really bad when I couldn't make it to things or be as involved as I could have been on that day or time.”

Why do you think doing research on brain disease matters?

“You know, brain disease is tragic in every way, shape, or form because, for obvious reasons, it affects everything you do.

When you watch someone like my husband, who had been so vibrant, so incredibly engaged and lively, this charismatic man who was speaking many times for the world when he was in the Senate. To watch him be ravaged by the disease, it's difficult and heartbreaking. It also made me dig my heels in and say, ‘This is enough, we have to stop this stuff and we have to be more engaged with funding for research to stop this.’ My neurologist and others involved get it, they are the tip of the spear and so I want to do anything I can do to help them and aid them and make it easier for them to do the work that they need to do and also spare any other family from going through what my family went through with my husband.”

How does the American Brain Foundation give you hope?

“I can't begin to tell you how it gives me hope. When I attend the meetings and when I am in on a call or whatever it may be and I hear all the things that are going on and I hear the thought processes and where to take this and what could happen and what is happening—it's hard for me to not stand up and dance around the room. Brain disease of any kind, be it migraines or glioblastoma, it affects an entire family. So, what the ABF does is not just help those that are afflicted by it but give them hope.

As I was saying, I don't want any other family to suffer the way we suffered and more importantly what they are doing not only gives hope but also lets me know that someone has our backs.

For the people that have been afflicted, folks like the ABF are working to help cure these diseases. I encourage everybody to get involved and support the ABF or any brain-related foundation to help us move forward and find cures to these horrible diseases.” 

Musician Peter Frampton

Our Community Is Strong!

Watch the messages of hope from musician Peter Frampton and other Brain & Life® cover celebrities who wish to inspire our Brain & Life community of people affected by neurologic disease and the neurologists who care for them as we confront the COVID-19 pandemic.

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Neurology Career Week Careers.aan.com

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

Academic Epileptologist (Specializes in Epilepsy Treatment) Cooper University Health Care Trenton, New Jersey.

Cooper University Health Care and Cooper Medical School of Rowan University are seeking a full-time academic epileptologist to join the Department of Neurology. This position will be based out of Trenton, NJ. Cooper provides the most advanced epilepsy care in the region, serving a large, diverse population with needs that range from common neurological conditions to the most complex.

Our team is committed to delivering high-quality patient care, community outreach, student and resident education, and clinical research. Our specialists work closely with our colleagues in neurosurgery, physical medicine and rehabilitation, psychiatry, and neuropsychology. We are a level 4 Epilepsy Center and offer the most complete epilepsy care, including surgery, neurostimulation, and care of the most complex patients. We have 4 adult epilepsy monitoring beds, superior equipment with trained and highly experience technologists. Applicants should

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AANnews • October 2020

be board-certified in neurology and have completed an epilepsy fellowship. Preference will be given to those demonstrating excellence in patient care, enthusiasm for medical student and resident education, and interest in clinical or translational research. This outpatient position does not involve hospital coverage or in house call. Candidates are eligible for a faculty appointment at a level commensurate with their experience and accomplishments at Cooper Medical School at Rowan University. Cooper University Health Care is the leading academic tertiary health care system and only statedesignated Level 1 Trauma Center in South Jersey, with clinical experts in more than 75 specialties. Cooper University Hospital is a 635-bed facility with over 7,500 employees, a network of more than 100 medical offices, and three urgent care centers throughout the region. The Department of Neurology has 24 providers and continues to expand. Cooper was the first Joint Commission Certified Comprehensive Stroke Center

in South Jersey. Email Bethann Mercanti at mercanti. bethann@CooperHealth.edu.  AANnews® Classified Advertising The AAN offers a complete package of print, online, and in-person recruitment advertising opportunities. Visit Careers.AAN.com for all AAN options, rates, and deadlines. d copy for the December 2020 print edition of A AANnews must be submitted by November 1, 2020. The same deadline applies to changes/ cancellations.

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

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. 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. 2. GOCOVRI® (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2020. 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.

Pharma Ad

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-0694 07/20

NIGHTTIME DOSING DOSING NIGHTTIME

DAYTIMEDAYTIME COVERAGE COVERAGE

With peak levels before the first morning levodopa dose1

GOCOVRI® MEANS THE DIFFERENCE

BETWEEN GETTING UP

AND GETTING OUT GOCOVRI® is ready when your Parkinson’s disease (PD) patients with dyskinesia need it.

A single nighttime dose gradually releases to reach peak levels in the morning, providing all-day coverage that decreases in the hours before bedtime.1 In clinical trials, GOCOVRI® reduced dyskinesia through Week 12 (primary endpoint measured by the UDysRS). It also reduced OFF time and increased “good” ON time (key secondary endpoints measured by patient diary entries).2*

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†

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“Good” ON time, ON time without troublesome dyskinesia; UDysRS, Unified Dyskinesia Rating Scale.

*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]). 2,3 † 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. 2

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-0694 07/20