2020 August AANnews

VOLUME 33 · ISSUE 8 · August 2020

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

AAN MOVES TO VIRTUAL CONFERENCES Same High-quality Education Delivered to You During COVID Crisis AAN conferences have a rich history of providing unparalleled education opportunities, the most cutting-edge scientific research, and an unmatched fostering of community. We know how important these conferences are to our members, but the safety of meeting attendees, faculty, exhibitors, and staff is paramount during the COVID pandemic. As such, your Academy is committed to developing conferences for the remainder of 2020 that address all of the critical needs upon which you’ve come to depend—in a new virtual environment! Beginning with SPORTS the recent Sports Concussion Conference, followed by CONCUSSION VIRTUAL CONFERENCE the Advanced Practice Provider Virtual Education Series beginning the week of August 10, and concluding with the always popular Fall Conference October 16–17, members can expect to find the same excellence they have come to AAN Advanced Practice Provider expect of our in-person conferences in a safe, interactive, Neurology Education Series 2020 and affordable virtual format. To make the virtual A Virtual Experience conferences even more accessible, all programming Virtual 2020 will be recorded and available to purchase for on-demand viewing post-event.

For more information on the Academy’s move to virtual conferences, visit AAN.com/conferencescommunity/regional-conferences. 

Virtual Education Series for Advanced Practice Providers to Kick off Week of August 10

Fall Conference to Go Virtual in October

AAN Advanced Practice Provider Neurology Education Series 2020

A Virtual Experience

A new, 10-week virtual education series designed especially for advanced practice providers (APPs) will kick off the week of August 10 and run through the week of October 12. Participants can expect to get overviews, updates, and resources on a variety of core topics in clinical neurology.

Continued on page 11

15 New Video Encourages Young People to Explore Neurology

Your Academy is bringing its highly popular Fall Conference to you this October 16–17!

As always, the Fall Conference will provide the timeliest clinical updates from noteworthy experts on the very hottest topics in neurology—now in a completely virtual setting. With the conference being near the end of the year, it also offers an excellent opportunity to fulfill CME requirements.

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18 Journal Article Examines Quality

Improvements to the Axon Registry

Virtual 2020

Continued on page 11

19 Brain Aneurysms Lead

Emilia Clarke to Help Others

›

NEW & APPROVED

FOR RELAPSING FORMS OF MS 1

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

DISCOVER THE FIRST AND ONLY S1P WITH NO FIRST-DOSE OBSERVATION REQUIRED1-3a FULL PRESCRIBING INFORMATION FOR ZEPOSIA HAS

NO FDO REQUIRED, NO GENETIC TESTING REQUIRED, AND NO OPHTHALMIC TESTING REQUIRED FOR MOST PATIENTS4b Start at ZEPOSIAhcp.com

Discover More About Once-Daily Oral ZEPOSIA POWERFUL EFFICACY 1c

COMPARABLE1,5-7e

CONSISTENT 7f

Proven superior in reducing relapses vs Avonexd

Safety profile vs Avonex in overall incidence of adverse reactions

Proven superior in reducing GdE and T2 lesions vs Avonex

Consistently low discontinuation rates vs Avonex

ZEPOSIA consistently maintained ALC near the lower limit of normal across 2 large-scale pivotal trials

Comparable rates of serious infections and malignancies vs Avonex 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 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.

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

ZEPOSIA is commercially available in the US as of June 1, 2020, following FDA approval on March 25, 2020.

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

a

b

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

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.

c

d

A relapse was defined as the occurrence of new or worsening neurological symptoms persistent 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

Adverse reactions: Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year were 59.8% and 75.5%, respectively, and at 2 years were 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of ≥2% for ZEPOSIA vs Avonex, respectively, were as follows: nasopharyngitis, 11.1% (vs 9.5%); alanine aminotransferase increased, 5.3% (vs 3.2%), gamma-glutamyl transferase increased, 4.5% (vs 1.2%); urinary tract infection, 4.1% (vs 3.1%); hypertension, 3.4% (vs 2.0%); pharyngitis, 3.2% (vs 2.3%); and respiratory tract infection viral, 2.4% (vs 1.2%).

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 1.0% vs 0.6% 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.

e

f

ALC: ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible retention of lymphocytes in lymphoid tissues. ZEPOSIA may therefore increase the susceptibility to infections.1 Mean ALC was 0.75 × 10 9 cells/L for both SUNBEAM and RADIANCE (at 1 year and 2 years, respectively).

ALC=absolute lymphocyte count; ARR=annualized relapse rate; CBC=complete blood count; ECG=electrocardiogram; FDO=first-dose observation; GdE=gadolinium enhancing; S1P=sphingosine-1-phosphate; VZV=varicella-zoster virus.

IMPORTANT SAFETY INFORMATION (CONTINUED) Infections (Continued): • 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, noncorticosteroid immunosuppressive, or immune-modulating 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

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

NEW & APPROVED

FOR RELAPSING FORMS OF MS 1

Start at ZEPOSIAhcp.com

IMPORTANT SAFETY INFORMATION (CONTINUED) 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 Prescribing Information.

References: 1. ZEPOSIA® (ozanimod) [package insert]. Summit, NJ: Bristol Myers Squibb; 2020. 2. Gilenya® (fingolimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. 3. Mayzent® (siponimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. 4. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017;13(6):375-382. 5. Comi G, Kappos L, Selmaj K, et al; for the 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. 6. Cohen JA, Comi G, Selmaj K, et al; for the 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. 7. Data on file, Bristol Myers Squibb.

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. 06/20 US-ZEP-20-0582

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.

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

Adverse Reactions

Upper respiratory infectionb elevationc

26

23

10

5

Orthostatic hypotension

4

3

Urinary tract infection

4

3

Back pain

4

3

Hypertensiond

4

2

Abdominal pain upper

2

1

Hepatic transaminase

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 · August 2020

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

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

New Fellows 14 Congratulations of the American Academy of

Neurology!

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

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

Neurology Is Subject 15 Sleep of New Continuum

The new issue of Continuum: Lifelong Learning in Neurology ® provides readers with the latest information on the neurology-related issues concerning sleep.

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

19

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

Clinical Practice Journal Adds Online ‘Practice Buzz’ Feature Neurology ® Clinical Practice has added a new feature for readers, “Practice Buzz.” This new section, a spin-off of “Practice Current," is designed to “give all neurological professionals worldwide a voice.”

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 Webinars for Neurology Departments

Research Programming for Trainees

Access the fourth webinar in a series of free webinars on the AAN YouTube channel (YouTube.com/AANchannel) for neurology department chairs and academic business administrators, covering reactivation of department activities post-COVID-19, focusing on education and training. Three more webinars will follow on addressing systemic racism, managing the financial repercussions of COVID-19, and resetting research operations amid COVID-19.

The AAN will offer monthly programming on research for medical students, residents, and fellows through 2020.

The Futures in Neurologic Research program will include virtual presentations as well as Q&A sessions covering themes such as Getting Your Feet Wet, Scientific Writing, Funding Means Freedom, and Recycle & Persevere in Grant Writing.

Contact Michelle Maxwell at mmaxwell@aan.com for more information. 

Conferences & Community

Virtual Education Series for Advanced Practice Providers to Kick off Week of August 10 Continued from cover

AAN Advanced Practice Provider Neurology Education Series 2020

“Advanced practice providers play a key role in the provision of clinical care for neurology patients in the outpatient and inpatient setting,” said Calli Cook, DNP, APRN, FNP-C, FAANP, co-director of the series. “This exciting new series will equip APPs with the latest information and strategies for providing the best care.”

A Virtual Experience

Each Tuesday, an email with resources and a preview of what is in store for the week will be sent to registered attendees.

The course video will go live Thursday of the same week, with five sessions featuring live Q&A with the presenters.

Programming will include: A Neurology Fundamentals live Q&A session with Jaffar Khan, MD, FAAN, on applying neuroanatomy to the clinical setting, with a summary of strategies to localize neurologic symptoms to specific area(s) of the central or peripheral nervous system, with application to clinical cases Neurodiagnostic Studies sessions summarizing the indications for and interpretation of commonly used neurodiagnostic studies, including neuroimaging, electromyography (EMG), and electroencephalography (EEG), with an emphasis on clinical correlations Common Clinical Topics sessions addressing common topics seen in clinical practice, including headache disorders, multiple sclerosis, epilepsy, and COVID-19 A session on alternative roles for APPs, in addition to clinical practice Opportunity to earn up to 6 CME credits across the series.

Networking opportunities through Town Hall Forums

Visit AAN.com/APP to learn more and register before August 6 to take advantage of discounted rates. 

Fall Conference to Go Virtual in October Highlights include: Keynote address on COVID-19 Neurology Update programs Practice Management talks 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

Continued from cover

Tips for the virtual NeuroExam Experiential talks, including Neuro Story Slam and NeuroJeopardy Continuum I and II Industry Pipeline talks Special networking opportunities for advanced practice providers, business administrators, and residents Virtual Exhibit Hall

Registration goes live mid-September, so visit AAN.com/20FC often for updates. 

AANnews • August 2020 11

President’s Column

AAN Board Accepts Recommendations to Improve Conditions for General Neurologists Nearly one-third of AAN physician members self-identify as general neurologists. This represents the largest subspecialty practice subset of membership. In addition, general neurologists have been particularly affected as members struggle to adapt to the changing health care landscape. Because they face challenges unique from our subspecialties, I appointed the General Neurology Task Force (GNTF) in October 2019 to examine these situations and concerns and make recommendations to the AAN Board of Directors.

For the purposes of discussions, the GNTF defined a general neurologist as: A neurologist who is comfortable evaluating and treating patients among the broad spectrum of neurological diseases and does not restrict their practice to a particular subspecialty.

Stevens

The GNTF was charged with addressing four major topic areas and identified areas of opportunity in each. In July, the task force presented the following recommendations to the Board of Directors to address each problem.

Topic 1: Needs of our population for general neurology care Review available neurology workforce data and collect supplemental data where gaps exist from the AAN’s 2013 Workforce Study, including neurologist shortages by subspecialty and general neurology.

Increase data collection and disseminate an annual report identifying member training and practice profiles, including practice type, patient mix, and subspecialty focus, across the career of neurologists beginning with first year out of training.

Enhance the AAN member profile and annual renewal/ new member applications to collect data on how a member self-identifies (generalist versus subspecialist) and time spent seeing general neurology patients versus primary subspecialty care.

Topic 2: General neurology in training programs Support efforts of the AAN’s Graduate Education Subcommittee (GES) in delaying fellowship application dates, including the support of the Fellowship Application Timing Initiative position statement.

Develop a framework that encourages balance of inpatient and outpatient neurology exposure, in particular early in residency training, including a careful look at ACGME requirements and how they impact this balance.

Require exposure throughout residency training to a diversity of general neurology practice settings including the community general neurology clinic. Other practice settings could include a community general neurology hospital-based consult service, in addition to the academic center-based continuity clinic, attending clinic, and inpatient neurology services.

Advocate for reducing financial barriers that cause limitations to increase general neurology practice exposure, including funding barriers between community neurology practices and training programs.

Develop case studies on mutually beneficial and financially viable relationships between community neurologists and academic centers to improve collaboration between the academic and community partnership.

Develop resources and enhance collaborations with the Academy’s pipeline initiatives, including increased exposure to general neurology through medical schools and clerkship programs, highlighting the profession and role of general neurology.

Evaluate the trend of available combined EEG/EMG neurophysiology fellowships in recent years and highlight this fellowship’s availability among residency programs.

Topic 3: The general neurology profession Define a general neurologist as a neurologist who evaluates and treats patients among the broad spectrum of neurologic diseases and does not restrict their practice to a particular subspecialty.

Encourage “general neurology” terminology to shift to “comprehensive neurology.”

Expand the AAN’s online educational offerings to focus an ongoing series of subspecialty updates for the general neurologist, including new therapeutics as they are released, to be disseminated across various AAN channels and presentation/discussions centralized in the AAN General Neurology Section.

Encourage practice models that provide work-life integration supporting the general neurologist across practice settings.

Create an AAN campaign highlighting the value and importance of general neurologists to membership and stakeholders.

Topic 4: General neurology at the AAN Expand both in-person and virtual opportunities to increase general neurologists’ involvement with the AAN, including Leadership Programs and other volunteer opportunities, as well as conference education and experiences.

Expand the AAN Practice Leadership Program to give community general neurologists increased opportunity to engage with the Academy.

Ensure member specialty representation is taken into consideration during the application review for all AAN Leadership Programs to include general neurology candidates.

Ensure appropriate representation of general neurologists on all major AAN committees.

Develop resources to navigate the educational and social aspects of AAN conferences for the general neurologist.

Develop a series of AAN awards dedicated to general neurologists, including but not limited to: An AAN Service Award dedicated to general neurologists who commit their time to AAN involvement and leadership Recognition of a general neurologist’s contributions to the community General neurologist representing exemplary academic and community partnership

Evaluate additional pathways to expand general neurologist qualifications for FAAN status.

Develop a method to continuously monitor general neurology engagement at the AAN, including the General Neurology Section.

I wish to thank Chair Michael E. Markowski, DO, FAAN; Vice Chair James N. Goldenberg, MD, FAAN; and the members of the GNTF for the thorough work they did in identifying solutions to these problems faced by general neurologists.

Over the coming months, AAN leadership and staff will review the recommendations and work with AAN committees on implementation strategies to help improve the working lives of these valued members. 

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

AANnews • August 2020 13

Conferences & Community

Congratulations New Fellows of the American Academy of Neurology!

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

Douglas L. Arnold, MD, FAAN Eric A. Awad, MD, FAAN Laxman Bahroo, DO, FAAN Sat Dev Batish, PhD, FAAN Firas Beitinjaneh, MD, FAAN Steve-Felix Belinga, MD, FAAN Andrea Calvo, MD, PhD, FAAN Paulo Eduardo Carrilho, MD, FAAN Amy S. Chappell, MD, FAAN Inwha Cho, MD, FAAN Meeryo Choe, MD, FAAN Nicolas Dupre, MD, FAAN Ramy El Khoury, MD, FAAN Eli Faria Evaristo, MD, FAAN Reda Badry Gad, MD, FAAN Na Tosha N. Gatson, MD, PhD, FAAN Bret C. Haake, MD, FAAN Marcel Hungs, MD, PhD, FAAN Justin T. Jordan, MD, MPH, FAAN Seth Kareus, MD, FAAN

Andrew Bruce Lassman, MD, FAAN Silvia F. Lumempouw, MD, FAAN Shalini Mahajan, MD, FAAN Rana H. Mahmood, MD, FAAN Aniel Q. Majjhoo, MD, FAAN Makoto Matsui, MD, PhD, FAAN Kasid Ahmed Nouri, MD, FAAN Roberto Padilla, MD, FAAN Mamatha Pasnoor, MD, FAAN Erica A. Schuyler, MD, FAAN David Shprecher, DO, FAAN Vincenzo Silani, MD, FAAN Amaal J. Starling, MD, FAAN Mark M. Stecker, MD, FAAN Paulus Sugianto, MD, FAAN Andrea S. Synowiec, DO, FAAN Nojan Valadi, MD, FAAN Natarajan Visvanathan, MD, DM, FAAN H.C. Weinstein, MD, FAAN 

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

Member Spotlight Video Shines on Leadership During COVID Crisis AAN members may now view the second in a series of Member Spotlight videos featuring President James C. Stevens, MD, FAAN, interviewing members who are living the values of the AAN in inspiring ways. The series is designed to highlight the “real life” stories of our members who, through their actions, clearly express the values of the AAN. In the latest video, Stevens interviews Korak Sarkar, MD, of Ochsner Health in New Orleans, who leveraged his 3D design expertise with local materials and fabrication resources to address a shortage of personal protective equipment—including shields, gowns, and sanitizers—at the onset of the COVID-19 pandemic. Sarkar is the clinical liaison for the all the individuals, task forces, and companies involved in the initiative that has delivered more than 100,000 face shield and 100,000 gowns in three months.

View the video at YouTube.com/AANchannel to see how Sarkar’s efforts tie closely the AAN’s values, particularly the value of leadership, where we guide, inspire, and

14

AANnews • August 2020

empower members and patients to make a positive difference in their lives and the lives of others in the neurology community. 

Education & Research

New Video Encourages Young People to Explore Neurology A new video produced by the AAN encourages young students to explore the field of neurology. The production is part of the Academy’s continuing campaign to entice students to consider a career in neurology by touting the many ways the specialty is helping improve lives. You can view “Make an Impact with Neurology” at AAN.com/ExploreNeurology.

We encourage you to share the video with children who love science and technology! 

Sleep Neurology Is Subject of New Continuum The new issue of Continuum: Lifelong Learning in Neurology® provides readers with the latest information on the neurology-related issues concerning sleep. Guest editor for the issue is Charlene Gamaldo, MD, FAAN, FAASM, and member of the AAN Board of Directors.

According to Gamaldo, “This issue examines new research links between sleep disorders and a number of neurologic conditions that include behavioral neurology, neurodegenerative, and neuroinflammatory conditions, as well as new approaches to both working up and managing sleep disorders that go far beyond sleep laboratories and sleep pharmacotherapies respectively.” Readers will feel “better equipped to discuss the latest evidence Gamaldo on sleep management and understand the latest evidence on the alternative treatments that patients may be seeking on their own accord to improve their sleep. Sleep is now seen by many patients as an important path towards achieving optimal (neurologic) health and wellness and this issue can help neurologists guide and counsel patients in achieving this goal.”

Topics include: Neurobiology and Neuroprotective Benefits of Sleep Logan Schneider, MD Evaluating the Sleepy and Sleepless Patient Raman K. Malhotra, MD, FAAN Central Disorders of Hypersomnolence Lynn Marie Trotti, MD, MSc Obstructive Sleep Apnea Douglas B. Kirsch, MD, FAAN Rapid Eye Movement Sleep Behavior Disorder and Other Rapid Eye Movement Parasomnias Michael J. Howell, MD, FAAN

Parasomnias Occurring in Non–rapid Eye Movement Sleep Michael H. Silber, MBChB, FAAN

Sleep in Patients with Neurologic Disease Sara E. Benjamin, MD

Restless Legs Syndrome and Other Common Sleep-related Movement Disorders Celia Garcia-Malo, MD; Sofia Romero Peralta, MD; Diego Garcia-Borreguero, MD, PhD

Sleep-wake Disorders in Childhood Amy Licis, MD, MSCI Rapid Eye Movement Sleep Behavior Disorder and Criminal Culpability for Acts Committed During an Episode Joseph S. Kass, MD, JD, FAAN; Rachel V. Rose, JD, MBA

Circadian Rhythm Sleep-wake Disorders Phyllis C. Zee, MD, PhD; Sabra M. Abbott, MD, PhD

Optimizing Behavioral Sleep Strategies Jason C. Ong, PhD; Charlene Gamaldo, MD, FAAN, FAASM

Insomnia Maria Nichole Perez, MD; Rachel Marie E. Salas, MD, MEdHP, FAAN

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. 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. 

AANnews • August 2020 15

Education & Research

Six Training Programs Achieve UCNS Accreditation Congratulations to the following six training programs that have attained accreditation by the United Council for Neurologic Subspecialties (UCNS) as of June 1, 2020: Behavioral Neurology & Neuropsychiatry Barrow Neurologic Institute at St. Joseph’s Hospital and Medical Center Meredith Wicklund, MD, program director Headache Medicine University of Texas at Austin/Ascension-Dell Medical School William Qubty, MD, program director Neurocritical Care

Houston Methodist Hospital Anh Nguyen, MD, program director Mercy Hospital at St. Louis Farid Sadaka, MD, program director Tulane University Aimee Aysenne, MD, MPH, program director

University of New Mexico Diana Greene-Chandos, MD, program director

Accreditation is a voluntary process of evaluation and peer review based on UCNS accreditation standards. Fellows who complete a UCNS-accredited program meet the training eligibility requirements to apply for certification in the subspecialty. There are currently 206 UCNS-accredited training programs in UCNS-recognized subspecialties.

Training programs interested in applying for accreditation will find application and program requirement information for each subspecialty under “Accreditation” at UCNS.org. Applications received by the December 1, 2020, deadline will be reviewed for accreditation in the spring of 2021. 

UCNS Continuous Certification Activities Approved for CME Credits United Council for Neurologic Subspecialties (UCNS) diplomates are now able to earn up to a maximum of 11 AMA PRA Category 1 credits™ for completing UCNS continuous-certification (C-cert) activities.

The C-cert activities include reading 10 designated subspecialty journal articles that represent the most important and recent developments in the subspecialty.

After reading the journal articles, diplomates must take and pass a 25-question online quiz that assesses the knowledge of the articles’ content.

UCNS diplomates will document their total credit hours during the online quiz process. Credits earned are based on the actual time spent completing the C-cert activities up to a maximum of 11 credit hours contingent on passing the C-cert quiz. Diplomates who complete their 2020 C-cert activities and pass the online quiz by November 30 will have a status of Certified-Meeting Requirements.

This UCNS C-cert activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of the American Academy of Neurology Institute and UCNS. The AAN Institute is accredited by the ACCME to provide continuing medical education for physicians.

For more information, visit UCNS.org. 

Tools & Resources

Epilepsy, Tremor, and More Featured in August Issue of Neurology: Clinical Practice As always, the new Neurology ® Clinical Practice provides an array of topics to spark the interest of readers.

The authors of “Disease Severity and Quality of Life in Homebound People with Advanced Parkinson Disease” conducted a pilot study on disease severity and quality of life (QoL) in homebound individuals with advanced Parkinson disease. They report high retention and satisfaction with quarterly interdisciplinary home visits and stabilization of QoL in an often-overlooked population.

Investigators evaluated a single case series of five patients with medication-refractory orthostatic tremor who were treated with bilateral VIM thalamic deep brain stimulation. In “Deep Brain Stimulation for Orthostatic Tremor,” they reveal patients experienced a modest increase of up to several minutes in standing time, which translated to meaningful improvement in standing activities of daily learning.

To better understand the clinical utility of serum antiepileptic drugs, researchers completed a systematic review of evidence supporting therapeutic drug monitoring (TDM) for antiepileptic drugs. Their analysis reported in “Clinical Utility of Therapeutic Drug Monitoring of Antiepileptic Drugs Systematic Review” shows TDM of at least some antiepileptic drugs can likely enhance the care of patients with epilepsy.

In “Diagnostic Experience Reported by Caregivers of Patients with Frontotemporal Degeneration,” researchers assessed the burden patients and caregivers face to obtain a frontotemporal degeneration (FTD) diagnosis. A survey of 698 caregivers of patients with FTD was analyzed, showing diagnostic delays,

with almost half of the surveyed patients reporting that they weren’t diagnosed until more than one year after they reported showing initial symptoms.

Other articles address the sustainability needs and financial barriers faced by epilepsy transfer and transition clinics and on diagnostic challenges concerning lumbar punctures and low-flow spinal arteriovenous fistulas.

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

Neurology Podcast: ®

PODCAST

20 Minutes Pack a Punch!

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

AANnews • August 2020 17

Tools & Resources

Journal Article Examines Quality Improvements to the Axon Registry The AAN’s Axon Registry ®, a neurology-specific quality improvement registry offered free to Academy members, helps members drive quality improvement for neurology and has ongoing processes that result in more accurate data for users.

An article published in the July 21, 2020, print issue of Neurology ®, “Implementation of a Data Accuracy Plan to Improve Data Extraction Yield in the Axon Registry,” examines a 2018 quality improvement project to improve the quality measure data mapping and key phrase logic in the registry.

This quality improvement article continues the 2017 registrylevel external validation that identified recommendations to help improve the registry and were reported in “Axon Registry ® Data Validation: Accuracy Assessment of Data Extraction and Measure Specification,” published on April 30, 2019. Both articles are available at n.Neurology.org.

The aim of the recent quality improvement project was to address two priorities identified by the external validation study: to improve methodology for mapping data from the electronic health record (EHR) systems into the clinical data record (CDR) and to improve key phrase logic for each measure. The AAN worked with the Axon Registry vendor, FIGmd Inc., to conduct an ongoing data quality improvement initiative (also referred to as the Data Accuracy Plan) to address both priorities.

that better consistency in documentation would improve data quality and precision of data capture. This consistency encompasses both the free-text vs. discrete field documentation as well as where the data is stored within the EHR system.” The data accuracy plan concluded Victorio that there was substantial improvement in the accuracy of data extraction for quality measure elements following intervention to improve methodology for mapping EHR data into the CDR and key phrase logic. Implementation of changes and continued review of data mapping and data dictionary are important to ensure accurate measure performance and improve reliability and validity of Axon Registry data.

For more information about the Axon Registry, visit AAN.com/ axon, or contact registry@aan.com with registry data and registry enrollment questions. 

The lead author of the article, M. Cristina Victorio, MD, FAHS, of Akron Children’s MEM: 20 FAAN Recruitment Ad—Half Page Horizontal> AN Hospital, said “We highlighted in this study Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

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

AAN.com/FAAN

Brain Aneurysms Lead Emilia Clarke to Help Others The cover story of the new issue of Brain & Life® profiles "Game of Thrones" actor Emilia Clarke, who sustained two brain aneurysms between 2011 and 2012 and subsequently founded a charity, SameYou, to help others recover from this serious brain disorder.

The COVID-19 pandemic remains a major concern, and Brain & Life continues to focus on publishing important information on how patients and caregivers can stay safe.

The second feature in this issue looks at the increase in posttraumatic stress disorder due to the pandemic. After months of sheltering in place and reading dire media reports about the economy, job losses, and the rising death toll, people are understandably traumatized. This article examines how individuals and society can get through this worldwide crisis.

The third feature explores how the different immune systems of men and women may account for the differences in death rates between the sexes and why women’s more robust immune system may explain why more women experience autoimmune diseases.

In the Take Charge department, patients and neurologists discuss the importance of self-care, especially in the context of a global pandemic. Additional articles look at how to hug during a pandemic, how COVID-19 is different from the flu, and how exercise can help one cope during this stressful period.

receive for your patients or update your clinic address, email BeGreen@WasteFreeMail.com. All members have online access to the magazine articles and additional resources at BrainandLife.org. Please share the website with your patients. 

AU G U S T/S E P

Mental Health Managing Pandemicrelated PTSD

TE M B E R 2 0 2 0

Safe Ways to Hug During COVID-19 Wellness Your Self-Care Checklist

Game Changer

Actor Emilia Cla

rke shares messa ge of hope with brain injury surviv ors during COVID -19

Brain & Life magazine is free for AAN members in the United States to distribute to patients, who also can subscribe for free. If you would like to adjust the number of copies you

Clinical Practice Journal Adds Online ‘Practice Buzz’ Feature Neurology ® Clinical Practice has added a new feature for readers, “Practice Buzz.” This new section, a spin-off of “Practice Current” and edited by Luca Bartolini, MD, and journal staff, is designed to “give all neurological professionals worldwide a voice.” It offers a wider variety of topics that relate to all in the clinical practice, such as physician assistants and nurse practitioners. Readers can weigh in with their views on each topic by participating in a brief survey.

Find “Practice Buzz” in the blog section at Neurology.org/practicebuzz/landing. 

AANnews • August 2020 19

Tools & Resources

Neurology Today and Brain & Life Win Major Publishing Awards The AAN’s publications Neurology Today ® and Brain & Life® both won top awards from the APEX editorial awards competition. The competition, which judges entries from the prior year, received 1,183 entries in a broad range of categories.

Neurology Today won the Grand Award—the top award category—for Writing for the September 5, 2019, article, “Professionalism—A Major Hospital Announces It Is Closing. The Fallout for Neurology Residents and Patient Services” (https://bit.ly/NT-Hahnemann).

Brain & Life won two Awards for Excellence in the category Interviews and Profiles, for the October/November 2019, article, “Actor Dash Mihok on How Tourette Syndrome Shaped His Career,” (brainandlife.org/ Mihok)and for Feature Writing for the August/September 2019 article, “Why MS Patients May Benefit from Aggressive Early Treatment” (brainandlife.org/ EarlyMSTreatment).  DEP: YY(Project Name) Ad—Half Page Horizontal> NJ, NCP Placed in Neurology Journal, or Neurology Clinical Practice 8.25 x 5.4375 +0.125 bleed, 4C

#NeurologyProud and proud to call the AAN my home.

Share why you are #NeurologyProud on social media.

Prepare Now for 2021 Outpatient E/M Coding Changes Beginning January 1, 2021, the way neurologists will document and submit claims for outpatient E/M services will change. The key changes are that the history and physical exam components will no longer be used in code selection while medical decision-making becomes the key non-time component, or the total time devoted to patient care on the date of service will be used for code selection. Also, additional time units of 15 minutes can be used for prolonged service and the new patient code 99201 will be eliminated.

While these changes are still months away, there are important considerations that should be reviewed now in order to prepare.

The nuances of the changes to the documentation guidelines for outpatient E/M services will be covered in future AAN resources, but in the interim it is important to first examine the way your practice currently uses the codes for office visit E/M services to fully understand how the changes will impact you.

Is your code choice for 99211–99215 Cohen codes heavily weighted to elements of history and physical examination and if so, how detailed are your charts as they related to medical decision-making?

Said Bruce H. Cohen, MD, FAAN, who serves as CPT adviser on the Coding and Payment Policy Subcommittee and is a member of the Health Policy Subcommittee, “This is a once in career opportunity for neurologists to alter the manner they document patient care, as these changes allow us to eliminate the duplicative or irrelevant documentation and focus on the issues, and be acknowledged for the time, that affects patient care.

However, we will need to focus on our written communication skills as they relate to medical decision-making documentation, but in the end, everyone will benefit from these changes.”

Or does your practice select the appropriate code based on time? (Current rules state that in order to bill an E/M visit based strictly on time, at least 50 percent of the encounter must be dedicated to counseling and coordination of care.)

A few questions to ask when examining your current practice or workflow are: What are your current billing patterns in terms of level of the encounter?

What is the breakdown of each level of service billed by your practice?

Does your practice select the appropriate code based on bullets or typical time/counseling and coordination of care to achieve each level?

How comfortable are you with the AMA Table of Risk in determining the complexity of Medical Decision Making?

How much non-face-to-face time are you typically spending on each patient encounter?

Do you use a template for documentation for each level of services?

It is important to keep in mind that only outpatient E/M services are impacted by the 2021 changes, including codes 99202–99205 and 99211–99215. As 2021 nears, it will be important to evaluate the pros and cons of each model: using the Medical Decision Making table of risk or total time to select the appropriate code.

Check AAN.com/EM often for new tools and resources to help you prepare. 

Article Examines Effects of Medicare NCS Reimbursement Reduction The Neurology ® journal published “The Effects of the Medicare NCS Reimbursement Policy: Utilization, Payments, and Patient Access” in its July 17, 2020, online issue.

The purpose of the study was to determine whether the 2013 nerve conduction study (NCS) reimbursement reduction changed Medicare utilization,

payments, and patient access to Medicare physicians. The work group performed a retrospective analysis of Medicare data (2012-2016 fee-for-service data from the CMS Physician and Other Supplier Public Use File).

69.3-percent fewer other specialists performing NCS, Medicare access to these physicians for E/M services was not affected. Increased autonomic and evoked potential testing may be an unintended consequence of the NCS reimbursement change. 

The study concluded that despite 21.1-percent fewer neurologists, 28.6-percent fewer physiatrists, and

AANnews • August 2020 21

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

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

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

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

ALWAYS

APPROXIMATELY

200,000

COMMITTED TO SAFETY

NEW PATIENTS

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

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

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

PATIENTS TREATED

1 IN 4

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

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

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

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

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

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

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

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

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

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

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

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

1.

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

2.

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

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

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

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

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

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

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

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

4.

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

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

5.

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

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

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

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Anti-JCV Antibody Negative

TYSABRI Exposure

<1/1,000

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

†

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 2:

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

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

Table 4:

TYSABRI n=627 %

Placebo n=312 %

38 27 19 5 5 4 3 3 2 2

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

21 17 11 10 9 8 7

17 16 9 6 7 7 5

19

16

16 5 2

14 3 1

11 10 5

10 9 4

12 7 4 1

9 4 2 0

5 3 2 2

4 <1 1 <1

6 2

5 <1

9 4

7 3

3 2 1

2 <1 <1

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

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

Table 3:

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

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

TYSABRI n=983 %

Placebo n=431 %

32 10 8 5 2 1

23 8 6 4 <1 <1

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

6 1

4 0

2

<1

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

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

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

TYSABRI n=214 %

Placebo n=214 %

37 11 6 4

31 6 3 <1

12 8 8 7

5 4 <1 3

7

5

4

2

12

8

6

3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Blood disorders: hemolytic anemia 8.

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

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

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

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

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

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

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

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

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

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

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

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

17.

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

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

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

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

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

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

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

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

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

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

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

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

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

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Policy & Guidelines

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

Immigration Restrictions Extended for Rest of 2020

Impact of COVID-19 on Research Funding Advocacy

On June 22, President Trump issued an order to temporarily suspend employment-based immigration to the United States.

This proclamation extends the previous order issued in April because of the public health and economic crisis caused by the coronavirus. Whereas health care professionals were exempt in the first order, the new restrictions, unfortunately, do not make the same exception explicitly.

Congress has passed significant legislation in response to COVID-19 that has included a total of $3.6 billion in emergency appropriations for the National Institutes of Health (NIH). The AAN has included research concerns in all our letters to Congress regarding COVID-19 legislation, and we support the Research Investment to Spark the Economy (RISE) Act, a bill that would authorize approximately $26 billion in supplemental grant funding to aid in research recovery.

Individuals “involved with the provision of medical care to individuals who have contracted COVID-19 and are currently hospitalized; are involved with the provision of medical research at United States facilities to help the United States combat COVID-19” are exempt. In addition, individuals already in the US or with a valid visa are not impacted by the new order.

Rulemaking to clarify the COVID-19 exemption qualifications, however, is still needed.

Under the order, H-1B visas and most J visas will be suspended through December 31, 2020. These visas allow US employers to temporarily hire skilled workers and for trainees to attend US academic programs. The move was made in response to the growing number of Americans out of work.

The lack of explicit protections for health care providers is a serious concern, and one the AAN will be closely monitoring to ensure the neurology workforce is not negatively impacted. As presently worded, these restrictions could also limit the entry of postdoctoral researchers and graduate students, further straining US biomedical and neuroscience research capacity.

The Academy recently endorsed the Healthcare Workforce Resilience Act (S. 3599/H.R. 6788). If passed, this bipartisan legislation would address the current green card backlog by reallocating unused visas for foreign-born physicians and foreign-born nurses to practice in the United States. In addition, this bill would waive the per-country caps on visa allocation.

The AAN is also continuing to advocate for our research funding priorities established prior to the pandemic. Every year Congress must authorize the amount of federal government spending before the start of fiscal year on October 1.

Lawmakers are beginning the process of “markup”—when they debate, amend, and rewrite the appropriations bills.

The first markup for Health and Human Services funding was scheduled on July 7.

Email your members of Congress to remind them of the importance of neurology research funding priorities.

Telehealth Advocacy The AAN has joined the efforts of coalitions sending comments to Capitol Hill regarding the recent telehealth expansions during the public health emergency. Most recently, the AAN joined more than 300 other organizations in signing a letter to congressional leadership from the Alliance for Connected Care.

The letter requested that Congress make permanent several telehealth priorities addressed in earlier COVID-19 legislative packages. 

AANnews • August 2020 29

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Dates & Deadlines

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AUGUST 1

Sports Concussion Conference AAN.com/SCC

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Registration Opens: Fall Conference AAN.com/20FC

Deadline: AAN Research Program Application AAN.com/ResearchProgram

AUGUST 3

OCTOBER 12–16

Deadline: UCNS Neuroimaging Certification Examination UCNS.org/NIcertification

Neurology Career Week Careers.AAN.com

AUGUST 10–OCTOBER 15

OCTOBER 13

Advanced Practice Provider Neurology Education Series AAN.com/APP

Early Registration Deadline: AAN Fall Conference AAN.com/20FC

AUGUST 31

OCTOBER 16–17

Deadline: Board Nominations AAN.com/nominations

AAN Fall Conference AAN.com/20FC

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.

Rutgers University-Brain Health Institute, Piscataway, New Jersey The Honorable Herbert C. and Jacqueline Krieger Klein have funded a new Endowed Chair in Neurodegeneration Research as part of the Rutgers University Brain Health Institute.

We seek a well-funded, accomplished clinician-scientist, at senior Associate Professor or Professor level, working in the field of Alzheimer’s disease and cognitive neurology. We are particularly interested in someone with experience in leading clinical trials to develop new therapeutics in this area. As a member of the Rutgers Biomedical and Health Sciences (RBHS) Department of Neurology, the faculty appointee will be expected to establish a clinical practice focused on Alzheimer’s disease and cognitive neurology. This faculty member would also lead as Director of the Krieger Klein Alzheimer’s Disease and Cognitive Neurology Clinical Research Center within the Rutgers Brain Health Institute. The Center will grow existing strengths in Alzheimer’s disease, cognitive neurology and related neurodegenerative disorders at Rutgers and facilitate translational and clinical research in Alzheimer’s disease and cognitive neurology. The ideal candidate will be a clinical research leader with a track record of a funded research program as it relates to Alzheimer’s disease and cognitive Neurology, who would dovetail with existing strengths at Rutgers in Alzheimer’s, Parkinson’s, cognitive neurology, multiple sclerosis, traumatic brain injury, epilepsy, spinal cord injury and other related research. Applicants must have an MD or MD/PhD degree, with demonstrated ability to apply for an independent NIH-funded clinical and translational research program. In addition to the $3 million Endowed Chair, we offer a competitive salary and substantial resources to develop a world-class Alzheimer’s Disease and Cognitive Neurology Clinical Research Center and to support the Director’s own clinical research activities. The clinical research activities will be facilitated by the newly formed Rutgers Health, an innovative, statewide academic health care provider organization across

New Jersey that brings together all Rutgers clinical activities and medical expertise to help hospitals expand and improve under one umbrella. The Rutgers University Behavioral delivery of medical offerings. Our board-certified specialty NCC: 20 Career Center Ad—Full Page> AANnews, NJ, NCP Placed in AANnews, or Neurology Clinical Practice Health Care (UBHC) with its unit, Comprehensive Services on Neurology Journal, neurologists work virtually alongside the local healthcare team 8.25 x 10.875 +0.125 bleed, 4C Aging (COPSA), include a multidisciplinary team of geriatric to ensure the highest quality care for patients. Benefits: Work psychiatrists, social workers, trainers and peer support from home anywhere in the US, Physician owned/physician lead, specialists who provide expert care and support for individuals Lucrative compensation model including benefits, Licensing, and their families dealing with memory loss. The COPSA credentialing, and malpractice coverage Health insurance Institute for Alzheimer’s Disease and Related Disorders is coverage. Requirements: ABPN certified in neurology, Inpatient a statewide program that includes the Memory Disorders stroke or neurohospitalist experience within the last year, Clinic, Care2Caregivers Helpline, Training and Consultation Licensure eligibility across the US. We strongly believe that Department. With a newly awarded NIH CTSA, Rutgers offers passion, innovation, and our forward-looking vision can bring unique opportunities to speed the translation of research substantial changes in the way patients are treated. Together discoveries into improved patient care. With two teaching with us, you will be able to broaden your knowledge, continue hospitals and over 250 neuroscience faculty labs in Newark, to improve patient outcomes and have a fantastic work/life New Brunswick and Piscataway, as well as proximity to the New balance. Email: smodjeska@tele-specialists.com  York, Princeton and Philadelphia neuroscience communities, Rutgers offers tremendous collaborative opportunities and A JOB TOP TALENT core facilities to support an active translational and clinical research program. Outstanding core facilities will support this position, including a new research-dedicated 3T MRI scanner and a human behavioral testing core in collaborationLearn with more! Careers.AAN.com Princeton University. In addition, Rutgers has the world’s largest university-based biorepository, RUCDR, which will facilitate genetic studies. Rutgers values a culturally diverse faculty; we strongly encourage applications from female and minority candidates. Applicants should submit a CV and statement of research accomplishments and plans and names of three to five references to Dr. Suhayl Dhib-Jalbut, MD, the Chair of the search committee, at bhi@ca.rutgers.edu

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FUNDING LIFELONG RESEARCH CAREERS

The American Brain Foundation believes in supporting the best and brightest early-career scientific researchers by advancing their innovative projects. More than 85% of the researchers supported by the American Brain Foundation have gone on to secure funding from the National Institutes of Health and other entities.

Researchers like Cindy Ly, MD, PhD. In 2016, Dr. Ly received the Foundation’s Clinical Research Training Scholarship in ALS. This funding launched her research career that today is funded by a National Institutes of Health K08 award. Dr. Ly’s research examines how misregulation of autophagy may lead to ALS.

Cindy Ly, MD, PhD

If you’re a researcher looking to make a difference in the lives of patients with brain disease, apply for our Next Generation Research Grants at AmericanBrainFoundation.org/For-Researchers