VOLUME 33 · ISSUE 11 · November 2020
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WE’RE HERE FOR YOU—RENEW FOR 2021 TO ENJOY ROBUST VIRTUAL OFFERINGS, STRONG COMMUNITY No Dues Increase for 2021 It’s time to renew your AAN membership for 2021. In the midst of the COVID-19 health care crisis, you can count on your Academy to be here for you to provide the same top-quality education, events, networking, and other programs and opportunities you’ve come to love—in new virtual formats that offer greater access and flexibility than ever.
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2021 E/M Coding Changes Will Allow Providers to Focus on Patients, Not Paperwork
November 30 Is Deadline to Apply for 2021 Diversity Leadership Program
By now, most health care providers are aware of the new rules affecting evaluation and management (E/M) services which take effect January 1, 2021. The AAN has supported these changes in part to reduce onerous documentation requirements and instead recognize the cognitive work of its members. Neurologists should keep in mind a few key points in terms of outpatient billing guidance: These changes apply only to new and established outpatient visits, and not inpatient billing Continued on page 23
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The American Academy of Neurology is committed to building leadership reflective of its diverse membership and patient population. In honor of this commitment, the Academy’s Diversity Leadership Program offers up to 10 AAN US member participants the opportunity to take part in an empowering and inspirational leadership development Continued on page 15
12 Commitment Made to Address Journals’ Gender Bias
26 Headache Quality Measures Updated, Published in Neurology
32 New NeuroReady Now Available for Advanced Practice Providers
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Discover an oral therapy for your patients with relapsing forms of multiple sclerosis (MS)1…
ZEPOSIA—FOCUSED ON WHAT COUNTS ZEPOSIA was studied in the largest number of patients with RMS in 2 pivotal head-to-head trials against an active comparator (N=2659)2,3a:
POWERFUL Efficacy1a
Proven superior in reducing relapses vs Avonexc Proven superior in reducing GdE and T2 lesions vs Avonex
COMPARABLE
Safety Profile vs Avonex in Overall Incidence of Adverse Reactions1-3b Consistently low discontinuation rates vs Avonex Comparable rates of serious infections and malignancies vs Avonex
Study designs: SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) were multicenter, randomized, double-blind, double-dummy, active treatment-controlled studies of daily oral ozanimod 0.46 mg (not approved for maintenance dose) or 0.92 mg vs weekly Avonex (interferon beta-1a), 30-μg intramuscular injection. Primary endpoint: ZEPOSIA reduced ARR vs Avonex by 48% at 1 year (0.18 vs 0.35, respectively) and by 38% at 2 years (0.17 vs 0.28, respectively). Secondary endpoints: ZEPOSIA reduced the number of new or enlarging T2 lesions by 48% at 1 year and by 42% at 2 years and reduced the number of GdE lesions vs Avonex by 63% at 1 year and 53% at 2 years. 9 of 10 patients showed no confirmed 3-month disability progression. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.1-3 b Adverse reactions: Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year was 59.8% and 75.5%, respectively, and at 2 years was 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of at least 2% in patients treated with ZEPOSIA and at least 1% greater than Avonex, respectively, were as follows: upper respiratory infection, 26% (vs 23%); hepatic transaminase elevation, 10% (vs 5%); orthostatic hypotension, 4% (vs 3%); urinary tract infection, 4% (vs 3%); back pain, 4%
a
The FIRST AND ONLY S1P With No First-Dose Observation Required1,4,5d
Full Prescribing Information for ZEPOSIA has NO FIRST-DOSE OBSERVATION required NO genetic testing required NO ophthalmic testing required for most patients6e
(vs 3%); hypertension, 4% (vs 2%); and abdominal pain upper, 2% (vs 1%). Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. Upper respiratory infection includes nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. Hepatic transaminase elevation includes alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminase increased. Hypertension includes hypertension, essential hypertension, and orthostatic hypertension. Overall discontinuation rates for ZEPOSIA vs Avonex at 1 year were 6% and 8%, respectively, and at 2 years were 10% and 15%, respectively. Discontinuation rates due to adverse reactions for ZEPOSIA vs Avonex at 1 year were 2.9% and 3.6%, respectively, and at 2 years were 3.0% and 4.1%, respectively. Serious infections: The rate of serious infections at 1 year for ZEPOSIA was 1.1% vs 0.7% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.9% for Avonex. Malignancy rates: The rate of malignancies at 1 year for ZEPOSIA was 0.2% vs 0% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.5% for Avonex.1-3
Indication ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
IMPORTANT SAFETY INFORMATION
Contraindications: • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization,
or Class III/IV heart failure or have a presence of Mobitz type II second or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, unless the patient has a functioning pacemaker • Patients with severe untreated sleep apnea • Patients taking a monoamine oxidase (MAO) inhibitor
Please see Important Safety Information throughout and Brief Summary of full Prescribing Information.
A relapse was defined as the occurrence of new or worsening neurological symptoms persisting for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.2,3
c
Start at ZEPOSIAhcp.com
Before initiating treatment with ZEPOSIA, all patients require a recent CBC including lymphocyte count (within 6 months or after discontinuation of prior MS therapy), an ECG to check for preexisting conduction abnormalities, a recent liver function test (within 6 months), and consideration of current and prior medications, including vaccinations.1 Patients without a confirmed history of varicella (chickenpox) or without documented VZV vaccination should be tested for antibodies. If VZV or other live attenuated immunizations are required, administer at least 1 month prior to initiation.1 For patients with a history of uveitis or macular edema, an ophthalmic assessment is required.1 An up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA, as a transient decrease in heart rate and atrioventricular conduction delays may occur.1
d
Diabetes mellitus and uveitis increase the risk of macular edema; patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation. A prompt ophthalmic evaluation is recommended if there is any change in vision while taking ZEPOSIA.1
e
ARR=annualized relapse rate; CBC=complete blood count; ECG=electrocardiogram; GdE=gadolinium enhancing; RMS=relapsing multiple sclerosis; S1P=sphingosine-1-phosphate; VZV=varicella-zoster virus.
IMPORTANT SAFETY INFORMATION (CONTINUED) Infections: ZEPOSIA may increase the susceptibility to infections. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
• Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. No cases of PML were identified in active-controlled MS clinical trials with ZEPOSIA. PML has been reported in patients treated with S1P receptor modulators and other MS therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation. If confirmed, treatment with ZEPOSIA should be discontinued • In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immunemodulating therapies used for treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA
Discover an oral therapy for your patients with relapsing forms of multiple sclerosis (MS)1…
ZEPOSIA—FOCUSED ON WHAT COUNTS IMPORTANT SAFETY INFORMATION (CONTINUED)
Start at ZEPOSIAhcp.com
Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • with significant QT prolongation • with arrhythmias requiring treatment with Class 1a or III anti-arrhythmic drugs • with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • with a history of Mobitz type II second-degree or higher AV block, sick-sinus syndrome, or sinoatrial heart block Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated Macular edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued Unintended Additive Immunosuppressive Effects From Prior Immunosuppressive or Immune-Modulating Drugs: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended Severe Increase in Disability After Stopping ZEPOSIA: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment so patients should be monitored upon discontinuation Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA Most common Adverse Reactions (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
Please see Important Safety Information throughout and Brief Summary of full Prescribing Information. References: 1. ZEPOSIA. Prescribing information. Bristol Myers Squibb; 2020. 2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X 3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8 4. Gilenya. Prescribing information. Novartis Pharmaceuticals Corporation; 2019. 5. Mayzent. Prescribing information. Novartis Pharmaceuticals Corporation; 2019. 6. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017;13(6):375-382. doi:10.1038/ nrneurol.2017.33
ZEPOSIA® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners. © 2020 Bristol-Myers Squibb Company. All rights reserved. Printed in the USA. 08/20 US-ZEP-19-0074
ZEPOSIA® (ozanimod) capsules, for oral use The following is a Brief Summary; refer to full Prescribing Information for complete product information. 1
• Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2)]
INDICATIONS AND USAGE
ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 2
DOSAGE AND ADMINISTRATION
2.1 Assessments Prior to First Dose of ZEPOSIA Before initiation of treatment with ZEPOSIA, assess the following: Complete Blood Count Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1)]. Cardiac Evaluation Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions (5.2)]. Liver Function Tests Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.3)]. Ophthalmic Assessment In patients with a history of uveitis or macular edema, obtain an evaluation of the fundus, including the macula [see Warnings and Precautions (5.7)]. Current or Prior Medications • If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. • Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating ZEPOSIA; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.3)]. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. 2.2 Dosing Information Maintenance Dosage After initial titration (see Treatment Initiation), the recommended maintenance dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8. ZEPOSIA capsules should be swallowed whole and can be administered with or without food. Treatment Initiation Initiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions (5.2)]. Table 1: Dose Titration Regimen Days 1-4
0.23 mg once daily
Days 5-7
0.46 mg once daily
Day 8 and thereafter
0.92 mg once daily
2.3 Reinitiation of ZEPOSIA After Treatment Interruption If a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment using the titration regimen [see Dosage and Administration (2.2)]. If a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned. 4
CONTRAINDICATIONS
ZEPOSIA is contraindicated in patients who: • In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2)]
• Have severe untreated sleep apnea [see Warnings and Precautions (5.2)] • Are taking a monoamine oxidase (MAO) Inhibitor [see Drug Interactions (7.7)] 5
WARNINGS AND PRECAUTIONS
5.1 Infections Risk of Infections ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. In Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA was similar to that in patients who received interferon (IFN) beta-1a (35% vs 34% and 1% vs 0.8%, respectively). ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes zoster [see Adverse Reactions (6.1)]. The proportion of patients who experienced lymphocyte counts less than 0.2 x 109/L was 3.3%. These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.
Herpes Viral Infection In Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below). Cryptococcal Infection Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. PML has been reported in patients treated with S1P receptor modulators and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, treatment with ZEPOSIA should be discontinued.
ZEPOSIA® (ozanimod) capsules, for oral use Prior and Concomitant Treatment with Anti-neoplastic, Immunosuppressive, or Immune-modulating Therapies In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. Antineoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects. Vaccinations Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur. No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. 5.2 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)]. ZEPOSIA was not studied in patients who had: • A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months • New York Heart Association Class III / IV heart failure • Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient’s health • Other pre-existing stable cardiac conditions without clearance from a cardiologist • Severe untreated sleep apnea • A resting heart rate less than 55 beats per minute (bpm) at baseline Reduction in Heart Rate Initiation of ZEPOSIA may result in a transient decrease in heart rate. In Study 1 and Study 2, after the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate of 1.2 bpm occurred at Hour 5 on Day 1, returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2)]. In Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. Atrioventricular Conduction Delays Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in Study 1 and Study 2 with dose titration, second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females) • With arrhythmias requiring treatment with Class 1a or Class III anti-arrhythmic drugs
• With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications (4)] 5.3 Liver Injury Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. In Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3 times the ULN within approximately 2-4 weeks. In clinical trials, ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, and ZEPOSIA should be discontinued if significant liver injury is confirmed. Individuals with an AST or ALT greater than 1.5 times ULN were excluded from Study 1 and Study 2. Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA, caution should be exercised when using ZEPOSIA in patients with a history of significant liver disease. 5.4 Fetal Risk There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm [see Use in Specific Populations (8.1)]. Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specific Populations (8.1)]. 5.5 Increased Blood Pressure In Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at the recommended doses. Because of an increased sensitivity to tyramine, patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA. 5.6 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in patients treated with ZEPOSIA as early as 3 months after treatment initiation. In pooled analyses of Study 1 and Study 2, the decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a (60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)), though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV1 or FVC after drug discontinuation. One patient discontinued ZEPOSIA because of dyspnea. Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated.
ZEPOSIA® (ozanimod) capsules, for oral use 5.7 Macular Edema S1P modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. In Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a. An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time if there is any change in vision while taking ZEPOSIA. Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. A decision on whether or not ZEPOSIA should be discontinued needs to take into account the potential benefits and risks for the individual patient.
B:11.125" T:10.875" S:9.875"
Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations. 5.8 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued. 5.9 Unintended Additive Immunosuppressive Effects From Prior Treatment with Immunosuppressive or Immune-Modulating Drugs When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions (7.1)]. 5.10 Severe Increase in Disability After Stopping ZEPOSIA Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriate treatment should be instituted, as required. 5.11 Immune System Effects After Stopping ZEPOSIA After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions (7.1)]. 6
ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling: • Infections [see Warnings and Precautions (5.1)] • Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.2)] • Liver Injury [see Warnings and Precautions (5.3)] • Fetal Risk [see Warnings and Precautions (5.4)] • Increased Blood Pressure [see Warnings and Precautions (5.5)] • Respiratory Effects [see Warnings and Precautions (5.6)] • Macular Edema [see Warnings and Precautions (5.7)] • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8)] • Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.9)] • Severe Increase in Disability After Stopping ZEPOSIA [see Warnings and Precautions (5.10)] • Immune System Effects After Stopping ZEPOSIA [see Warnings and Precautions (5.11)]
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies in which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14)]. Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. Table 2: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than IFN beta-1aa (Pooled Study 1 and Study 2)
Adverse Reactions
Studies 1 and 2 ZEPOSIA IFN beta-1a 0.92 mg 30 mcg (n=882) Intramuscularly % Once Weekly (n=885) %
Upper respiratory infectionb
26
23
Hepatic transaminase elevationc
10
5
Orthostatic hypotension
4
3
Urinary tract infection
4
3
Back pain
4
3
Hypertensiond
4
2
Abdominal pain upper
2
1
a
Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. c Includes the following terms: alanine aminotransferase increased, gammaglutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminases increased. d Includes hypertension, essential hypertension, and orthostatic hypertension. Reduction in Heart Rate Initiation of ZEPOSIA may result in transient decrease in heart rate [see Warnings and Precautions (5.2)]. Respiratory Effects Dose-dependent reductions in absolute FEV1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.6)]. Malignancies Malignancies, such as melanoma, basal cell carcinoma, breast cancer, and seminoma, were reported with ZEPOSIA in the active-controlled trials for ZEPOSIA. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator. Hypersensitivity Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials. 7
DRUG INTERACTIONS
7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies ZEPOSIA has not been studied in combination with anti-neoplastic, immunemodulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1)]. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.9)].
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 · November 2020
November Highlights The Mission of the AAN is to promote the highest quality patient-centered neurologic care and enhance member career satisfaction.
Demonstrates Respect for 13 Member Homeless Through Unique Program
The fourth in a series of Inspirational Member Spotlight videos of AAN members living the values of the AAN in inspiring ways features President James C. Stevens, MD, FAAN, interviewing Joy Ding, MD, who is treating homeless neurology patients with her colleague and senior neurologist Chris Skinner, MD.
The Vision of the AAN is to be indispensable to our members. Contact Information American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415 Phone: (800) 879-1960 (toll free) (612) 928-6000 (international) Email:
memberservices@aan.com
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AAN Chief Executive Officer: Mary E. Post, MBA, CAE
Editor-in-Chief: Melissa W. Ko, MD, FAAN, CPE Managing Editor: Angela M. Babb, MS, CAE, APR Editor: Tim Streeter Writers: Ryan Knoke and Sarah Parsons Designer: Siu Lee Email: aannews@aan.com AANnews® is published monthly by the American Academy of Neurology for its 36,000 members worldwide. Access this magazine and other AAN publications online at AAN.com. The American Academy of Neurology ’ s registered trademarks and service marks are registered in the United States and various other countries around the world. “American Brain Foundation” is a registered service mark of the American Brain Foundation and is registered in the United States. The inclusion of advertisements and/or promotions of Sponsors and other Internet sites or resources that offer content, goods, or services on the Website does not imply endorsement of the advertised/promoted products or services by AAN.
Realizes the Power 14 Graduate and Value of Mentorship
A truly great mentor shares his or her own career path; provides guidance, motivation, emotional support, and role modeling; and even helps the mentee explore careers, set goals, develop contacts, and identify resources. In her experience with the 2016 AAN Medical Student Diversity Leadership Program, Daniella C. Sisniega, MD, hit the mentor jackpot.
24 Coming for 2021
New Axon Registry Measures The AAN's neurology-specific quality measurement sets are designed to help improve the care of your patients. They are integrated with the Academy’s Axon Registry ®—a free member benefit—to help members report for the Merit-based Incentive Payment System (MIPS).
News Briefs Participate in Virtual Career Fair The Neurology Career Center’s new Virtual Career was moved to November 5 and 6 to accommodate greater than anticipated demand. Upload your CV to the Neurology Career Center site at Careers.AAN.com and let employers find you! Just sign in as a job seeker and then select “Your Profile” from the top menu. From here, you can upload your CV and manage who can view your profile. For a limited time, members can receive a free reflex hammer by creating a new job seeker profile on the Neurology Career Center site by November 6 (while supplies last).
Attend Post-election Webinar A post-election webinar is scheduled for November 18 from 7:00 p.m. to 8:00 p.m. CT. Visit AAN.com for registration details.
Welcome New Palliative Care Section With the newly formed Palliative Care Section, the AAN now has 40 Sections. The Pain and Palliative Care Section has split into two sections. The Palliative Care Section, chaired by Jessica Besbris, MD, is designed for practicing palliative neurologists, neurologists interested in learning more about palliative care, trainees exploring their options, and others with interest in palliative care. Visit Synapse.AAN.com to learn more and join the section.
President’s Column
Task Force Proposes Strategy for Stronger Engagement with Patients and Public As I wrote in this space last March, one of the eight goals of the AAN’s 2020 strategic plan is to “increase the reach of AAN resources to enhance patient-centered neurologic care.” By doing so, the AAN can help demonstrate the value of neurologists to the public; help members educate their patients on neurologic disease; and leverage the power of patients and their stories to help us advocate on Capitol Hill. We can be proud the AAN is far beyond other medical associations in its vast support of very sophisticated patient education tools to members. The remarkable quality of our flagship patient education magazine Brain & Life® and its companion website BrainandLife.org have attracted major celebrities to appear on the cover and in videos sharing their personal neurology stories. Our quarterly Spanish-language Brain & Life® en Espanol reaches an important, previously untapped segment of the public, and our series of diseasespecific books guide patients to healthier, fulfilling lives. These initiatives have added tremendous value to our members and your ability to provide trusted content to your patients. We want to build on our success because we recognize there’s great potential to increase our reach. But first we must determine how best to evolve our efforts to provide even greater value to members and the patients they serve. Consequently, last February I created the Patient-Public Strategy Task Force, chaired by President Elect Orly Avitzur, MD, MBA, FAAN, to devise a strategy to achieve this goal in 2020 and beyond by evaluating current initiatives and addressing the following questions: How can we better engage/inform our patients and the public with AAN resources currently available? How can we mobilize patients/public to advocate for issues critical to our profession through current products and new initiatives? How can we collaborate with strategic partner organizations to accomplish AAN goals? Provide a one-, three-, and five-year plan along with metrics for success. Dr. Avitzur and the task force presented their final report to the Board during its September meeting, and what follows is a summary of their recommendations. A Be the Hub in the Neurologic Community The AAN has already invested significant resources and developed expertise in creating high-quality patient and public products, programs, and services to educate the public. An overarching recommendation of the task force is that all efforts should continue to build the AAN and Brain & Life as the premier organization and brand that owns brain health.
B Produce Trustworthy Patient and Public Education Resources
Stevens
The AAN has established proficiency in developing high-quality, neurologistvetted patient and public resources. Recommendations are geared toward greater inclusivity of patients and the public as well as leveraging new technologies to deliver virtual programming to a wider audience. C Expand Patient and Public Advocacy The AAN has experienced success with limited patient and public advocacy efforts by including individuals in the Neurology on the Hill event and through sign-on letters and patient advocacy group coordination efforts. That said, there is a significant opportunity to leverage new and existing public audiences to advance AAN advocacy efforts in a coordinated manner. D Strengthen the Appeal of Neurology as a Field Significant investment has been made by the AAN to increase the awareness and appeal of the field of neurology and to provide neuroscience education to students in kindergarten through medical school. Additional commitment through multiyear plans, with measurable outcomes, will strengthen the pipeline as populations age and the need for care increases. The Board of Directors accepted the task force’s report with deep gratitude for the hard work and creative responses— particularly during these challenging past months. The report is now with CEO Mary Post and her executive team to prioritize strategies and tactics for 2021, make assignments for implementation, and report back to the president and Board of Directors on their decisions. Please join me in thanking Dr. Avitzur and the Patient-Public Strategy Task Force for responding to the AAN’s demands on their time and energy and providing thoughtful guidance for these new initiatives.
James C. Stevens, MD, FAAN President, AAN jstevens@aan.com @JimStevensMD on Twitter
AANnews • November 2020 11
Conferences & Community
Commitment Made to Address Journals’ Gender Bias Affirming that “The underrepresentation of women in medical journals has consequences for the scientific field, journals, women researchers, and future generations of clinicians and scientists,” a paper from lead author and Neurology ® Editor-in-Chief José G. Merino, MD, MPhil, FAHA, FAAN, reveals the gender dichotomy across the AAN’s scientific publications and the steps that are being taken to rectify the situation. The paper—“Neurology’s Commitment to Address Gender Bias in Neurology Journals” published ahead of print in Neurology on August 4, 2020—examines the numerous gender disparities in academic medicine, including the fact that in 2018, only 14 women chaired one of the 129 neurology departments in the US. In the field of neurology journals, women comprised only 12 percent of editors-in-chief, 23 percent of associate editors, and 21 percent of editorial board members across 247 publications.
4. Invite more women to review papers so that by the end of June 2021, the proportion of female peer reviewers Merino will have increased from 30 percent to 40 percent and to 50 percent by the summer of 2022. 5. Immediately increase the proportion of women invited to write editorials and commentaries from 37 percent to 50 percent. 6. Work with the editors of the three spoke journals in the Neurology family (Neurology® Clinical Practice; Neurology® Neuroimmunology & Neuroinflammation; and Neurology ® Genetics) to achieve gender balance among editors and the editorial boards of these journals over the next three years. Women make up 14 percent to 38 percent of the editorial boards of these journals.
The detrimental effects of excluding women from key roles in medical journals include depriving the field of their expertise and perspective and limiting career advancement opportunities and could threaten their future research funding and even financial future. In addition, exclusion diminishes role models for future generations of women. To achieve gender parity among our editorial team, peer reviewers, and invited authors, we commit to taking the following six steps: 1. Increase the proportion of women appointed to the editorial board from 27 percent to 35 percent this year and to 50 percent by 2023. 2. Increase the number of women among editors in our masthead from 34 percent to 50 percent by next summer.
New processes will be employed to track progress on these issues. Journal leadership also plans to implement similar policies to ensure proportionate representation of people from racial and ethnic groups that are underrepresented in medicine, as well as to continue to strive for a strong international representation on our editorial board. To read the paper, visit n.Neurology.org.
3. Increase the proportion of women editors of the Resident & Fellow Section (RFS) from 27 percent to 50 percent this year so that the RFS board reflects the current state of neurology residency programs.
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AANnews • November 2020
Member Demonstrates Respect for Homeless Through Unique Program Their efforts exemplify the AAN’s value of Respect: “We embrace the dignity and uniqueness of every person, being sensitive and empathetic to the needs of others.” This and previous spotlight videos that show how members are demonstrating AAN values can be seen in a playlist on the AAN YouTube channel at YouTube.com/AANchannel
The fourth in a series of Inspirational Member Spotlight videos of AAN members living the values of the AAN in inspiring ways is now available for viewing. It features President James C. Stevens, MD, FAAN, interviewing Joy Ding, MD, who is treating homeless neurology patients with her colleague and senior neurologist Chris Skinner, MD. Their program, Neurons on Wheels (NOW) is carried out through an organization called Ottawa Inner City Health. Until a few years ago, the program had no regular consultant neurology services. As a second-year resident, Ding signed on for a month-long elective with the program and accompanied the organization’s cofounder, who is the Ottawa Hospital chief of staff. Realizing that patients could benefit from a regular consulting neurology service, Ding and Skinner held their first outpatient neurology clinic at a shelter in late 2015. Since then, they have maintained monthly clinics with to inIstrpyir e neurologists coming to the patients. hpaevoeple who
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Graduate Realizes the Power and Value of Mentorship To a promising young neurologist, a mentor can make all the difference in establishing career trajectory—and success. A truly great mentor shares his or her own career path; provides guidance, motivation, emotional support, and role modeling; and even helps the mentee explore careers, set goals, develop contacts, and identify resources. In her experience with the 2016 AAN Medical Student Diversity Leadership Program, Daniella C. Sisniega, MD, hit the mentor jackpot. “I met incredible mentors, lifelong friends, and colleagues,” said Sisniega, who is currently a third-year neurology resident at Mount Sinai Hospital in New York City, and in the process of applying to a neurocritical care fellowship. “I also learned more about the field of neurology and my mentors’ incredibly interesting career paths.” Having realized the power of great mentorship and networking, in the years since graduating from the program Sisniega has taken it upon herself to actively seek out mentors in neurology who have subsequently proven invaluable to her continued professional development. “With their advice and support, I have gained the confidence to go out of my comfort zone and participate in a variety of projects, which I presented in many conferences, including two AAN Annual Meetings and a conference in Japan!” Sisniega was also awarded the Boston University Medical Student Neurology Research Award, which is presented to a fourth-year medical student who has excelled in the area of research. But it is as an educator where Sisniega has found some of her greatest post-leadership program successes, where mentee has turned mentor. “The Medical Student Diversity Leadership Program taught me not only the importance of having good mentors, but also how important it is to mentor minority students to cultivate their interest in neurology,” said Sisniega, who is currently doing some mentoring of her own to high school students
of underrepresented minorities with an interest in medicine and neuroscience. “I learned how important it is to do our best to diversify our field,” she explained, “and I [am using] the skills I learned in the leadership program—such as goal setting, identifying resources, developing an action plan—to create a program to increase pre-clinical medical student exposure to vascular neurology and, hopefully, increase their interest in neurology.”
Sisniega
The project exposes medical students to stroke codes and thrombectomies, stroke imaging, and the clinical assessment and treatment of the stroke patient. “I am proud to say that this project has been very successful and has been accepted to the HarvardMacy Program for Post-Graduate Trainees this December. I am hoping to develop this into a clinical elective for third- and fourthyear students in the future, who wish to increase their exposure to neurology beyond what is already offered in the neurology clerkship.” Added Sisniega, “With the support of my mentors, I hope to continue to develop as a clinician, researcher, and educator.” The Medical Student Diversity Leadership Program offers up to 10 US medical students from underrepresented racial and ethnic backgrounds in medicine the opportunity to participate in a fiveday directed leadership program to explore career options in the field of neurology, and gain access to mentors during the AAN Annual Meeting. This exposure to neurology's best and brightest and the intense educational experience are intended to make neurology a more attractive career option. Learn more at AAN.com/view/MSD.
Sisniega Featured in AAN Member Spotlight Series
Daniella C. Sisniega, MD, recently shared with President James C. Stevens, MD, FAAN, her experience working at one of the hardest-hit hospitals in New York during the COVID-19 pandemic. You can watch the interview on the AAN’s YouTube channel at YouTube.com/AANChannel.
14
AANnews • November 2020
November 30 Is Deadline to Apply for 2021 Diversity Leadership Program
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experience designed to engage and hone leadership skills among neurologists from underrepresented groups. Applications are currently open until November 30 for this all-expenses-paid program that will kick-off virtually in January 2021, with an in-person graduation in September 2021. Through partnership with established AAN leaders and nationally recognized leadership experts, participants will receive personalized “The AAN's Diversity Leadership Program has given me the opportunity coaching and leadership development training to better understand what is indispensable for a successful career by an executive consultant; individualized as a physician and leader in our field. This program has revealed how mentoring by a neurology leader; and an AAN essential it is to align my passions and core values, as well as my Board-assigned group project and presentation personal vision and life mission, to the strategic implementation of to the AAN Board of Directors. Board-assigned actionable plans that will result in equitable health care, which is my group projects often inform strategic direction, goal. Truly, I feel blessed and I am grateful for my participation and and one such project resulted in the formation collaboration with other leaders in our field. I urge physicians who of the Joint Coordinating Council on Equity, identify as underrepresented in medicine to apply!!” Diversity, and Inclusion. —Clarimar Borrero-Mejias, MD Visit AAN.com/DLP to apply by November 30. CESC: 20APP Registration Print Ad—Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C
AAN Advanced Practice Provider Neurology Education Series 2020
A Virtual Experience
Virtual education series designed by advanced practice providers especially for neurology advanced practice providers Access Now at AAN.com/APP
FOR PATIENTS WITH RELAPSING FORMS OF MS
PLAYING WITH FEWER RELAPSES • The efficacy of VUMERITY® (diroximel fumarate) is based upon bioavailability studies in patients with relapsing forms of multiple sclerosis and healthy subjects comparing dimethyl fumarate to VUMERITY1 • In Study 1 and Study 2 pivotal trials, dimethyl fumarate demonstrated a 53% and 44% relative reduction in annualized relapse rate (ARR) vs placebo, respectively (0.172 vs 0.364; P<0.0001), (0.224 vs 0.401; P<0.0001)1
Indication
• Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present
Important Safety Information
Herpes Zoster and Other Serious Opportunistic Infections • Serious cases of herpes zoster have occurred in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY), including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on VUMERITY for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered • Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment • Consider withholding VUMERITY treatment in patients with herpes zoster or other serious infections until the infection has resolved
VUMERITY® (diroximel fumarate) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
CONTRAINDICATIONS VUMERITY is contraindicated in patients • With known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY. Reactions may include anaphylaxis and angioedema • Taking dimethyl fumarate
WARNINGS AND PRECAUTIONS Anaphylaxis and Angioedema • VUMERITY can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in patients taking dimethyl fumarate (which has the same active metabolite as VUMERITY) have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue VUMERITY and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema Progressive Multifocal Leukoencephalopathy • Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate (which has the same active metabolite as VUMERITY). PML is an opportunistic viral infection of the brain caused by the JC virus ( JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial • PML has occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9 × 10 9/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8×10 9/L persisting for more than 6 months • At the first sign or symptom suggestive of PML, withhold VUMERITY and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes
© 2020 Biogen. All rights reserved. 09/20 VUM-US-0458 v2
Lymphopenia • VUMERITY may decrease lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (which has the same active metabolite as VUMERITY), mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with dimethyl fumarate or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 109/L or ≤0.5 x 10 9/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years) • In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced lymphocyte counts <0.5 x 10 9/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. Neither VUMERITY nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts
Full access to Biogen Support Services • Helping patients start treatment, manage common side effects, and navigate financial assistance
Learn more about additional studies on VUMERITY in RRMS patients2,3
Visit www.vumerityhcp.com
RRMS=relapsing-remitting multiple sclerosis.
• Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with VUMERITY, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of VUMERITY in patients with lymphocyte counts less than 0.5 x 10 9/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if VUMERITY is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution Liver Injury
• Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY) in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients • Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials with dimethyl fumarate • Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during treatment as clinically indicated. Discontinue VUMERITY if clinically significant liver injury induced by VUMERITY is suspected Flushing
• VUMERITY may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials of dimethyl fumarate (which has the same active metabolite as VUMERITY), 40% of dimethyl fumarate-treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization
ADVERSE REACTIONS • The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate (which has the same active metabolite as VUMERITY) were flushing, abdominal pain, diarrhea, and nausea • Gastrointestinal adverse reactions: Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with dimethyl fumarate compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with dimethyl fumarate • Hepatic transaminases: An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate was seen primarily during the first six months of treatment and most patients with elevations had levels <3 times the upper limit of normal (ULN) during controlled trials. There were no elevations in transaminases ≥ 3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with dimethyl fumarate or placebo • Eosinophilia adverse reactions: A transient increase in mean eosinophil counts was seen during the first 2 months of therapy
USE IN SPECIFIC POPULATIONS Renal Impairment • No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite, use of VUMERITY is not recommended in patients with moderate or severe renal impairment Please see following pages for Brief Summary of full Prescribing Information. Study Designs • Study 1: A 2-year, randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. Secondary endpoint: ARR. • Study 2: A 2-year, multicenter, randomized, double-blind, placebo-controlled study in 1417 patients with RRMS. Primary endpoint: ARR. References: 1. VUMERITY Prescribing Information, Biogen, Cambridge, MA. 2. Naismith RT, et al. CNS Drugs. 2020;34(2):185-196. doi:10.1007/ s40263-020-00700-0 3. Naismith RT, et al. Mult Scler. Published online November 4, 2019. doi:10.1177/1352458519881761
VUMERITY® (diroximel fumarate) delayed-release capsules, for oral use of the brain caused by the JC virus (JCV) that typically only occurs Brief Summary of full Prescribing Information in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who 1. INDICATIONS AND USAGE received dimethyl fumarate for 4 years while enrolled in a clinical trial. VUMERITY is indicated for the treatment of relapsing forms of multiple During the clinical trial, the patient experienced prolonged lymphopenia sclerosis (MS), to include clinically isolated syndrome, relapsing- (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years) while remitting disease, and active secondary progressive disease, in adults. taking dimethyl fumarate [see Warnings and Precautions (5.4)]. The patient had no other identified systemic medical conditions resulting 2. DOSAGE AND ADMINISTRATION in compromised immune system function and had not previously 2.1 Blood Tests Prior to Initiation of VUMERITY been treated with natalizumab, which has a known association with Obtain the following prior to treatment with VUMERITY: PML. The patient was also not taking any immunosuppressive or • A complete blood cell count (CBC), including lymphocyte count immunomodulatory medications concomitantly. [see Warnings and Precautions (5.4)] PML has also occurred in patients taking dimethyl fumarate in the • Serum aminotransferase, alkaline phosphatase, and total bilirubin postmarketing setting in the presence of lymphopenia (<0.9 × 109/L). levels [see Warnings and Precautions (5.5)] While the role of lymphopenia in these cases is uncertain, the PML 2.2 Dosing Information cases have occurred predominantly in patients with lymphocyte counts The starting dosage for VUMERITY is 231 mg twice a day orally. After <0.8×109/L persisting for more than 6 months. 7 days, the dosage should be increased to the maintenance dosage At the first sign or symptom suggestive of PML, withhold VUMERITY of 462 mg (administered as two 231 mg capsules) twice a day orally. and perform an appropriate diagnostic evaluation. Typical symptoms Temporary dosage reductions to 231 mg twice a day may be considered associated with PML are diverse, progress over days to weeks, and for individuals who do not tolerate the maintenance dosage. Within include progressive weakness on one side of the body or clumsiness 4 weeks, the recommended dosage of 462 mg twice a day should of limbs, disturbance of vision, and changes in thinking, memory, and be resumed. Discontinuation of VUMERITY should be considered orientation leading to confusion and personality changes. for patients unable to tolerate return to the maintenance dosage. Magnetic resonance imaging (MRI) findings may be apparent before Administration of non-enteric coated aspirin (up to a dose of 325 mg) clinical signs or symptoms. Cases of PML diagnosed based on MRI 30 minutes prior to VUMERITY dosing may reduce the incidence or findings and the detection of JCV DNA in the cerebrospinal fluid in severity of flushing [see Clinical Pharmacology (12.3)]. the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with 2.3 Administration Instructions Swallow VUMERITY capsules whole and intact. Do not crush or chew, PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent or sprinkle the capsule contents on food. If taken with food, avoid a high-fat, high-calorie meal/snack; the with PML may be useful, and any suspicious findings should lead to meal/snack should contain no more than 700 calories and no more than further investigation to allow for an early diagnosis of PML, if present. 30 g fat [see Warnings and Precautions (5.6) and Clinical Pharmacology Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with (12.3)]. PML in patients with PML who were initially asymptomatic compared to Avoid co-administration of VUMERITY with alcohol [see Clinical patients with PML who had characteristic clinical signs and symptoms Pharmacology (12.3)]. at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in 2.4 Blood Tests to Assess Safety After Initiation of VUMERITY Obtain a complete blood cell count (CBC), including lymphocyte count, disease in these patients. 6 months after initiation of VUMERITY and then every 6 to 12 months 5.3 Herpes Zoster and Other Serious Opportunistic Infections thereafter, as clinically indicated [see Warnings and Precautions (5.4)]. Serious cases of herpes zoster have occurred in patients treated Obtain serum aminotransferase, alkaline phosphatase, and total with dimethyl fumarate (which has the same active metabolite as bilirubin levels during treatment with VUMERITY, as clinically indicated VUMERITY) including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster [see Warnings and Precautions (5.5)]. meningomyelitis. These events may occur at any time during treatment. 2.5 Patients With Renal Impairment Monitor patients on VUMERITY for signs and symptoms of herpes No dosing adjustment is recommended in patients with mild renal zoster. If herpes zoster occurs, appropriate treatment for herpes zoster impairment. should be administered. VUMERITY is not recommended in patients with moderate or severe Other serious opportunistic infections have occurred with dimethyl renal impairment [see Use in Specific Populations (8.6) and Clinical fumarate, including cases of serious viral (herpes simplex virus, Pharmacology (12.3)]. West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium 3. DOSAGE FORMS AND STRENGTHS VUMERITY is available as hard, delayed-release capsules containing tuberculosis) infections. These infections have been reported in 231 mg of diroximel fumarate. The capsules have a white cap and a patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, white body, printed with “DRF 231 mg” in black ink on the body. meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and 4. CONTRAINDICATIONS ear. Patients with symptoms and signs consistent with any of these VUMERITY is contraindicated in patients infections should undergo prompt diagnostic evaluation and receive • With known hypersensitivity to diroximel fumarate, dimethyl appropriate treatment. fumarate, or to any of the excipients of VUMERITY. Reactions Consider withholding VUMERITY treatment in patients with herpes may include anaphylaxis and angioedema [see Warnings and zoster or other serious infections until the infection has resolved [see Precautions (5.1)]. Adverse Reactions (6.2)]. • Taking dimethyl fumarate [see Drug Interactions (7.1)]. 5.4 Lymphopenia 5. WARNINGS AND PRECAUTIONS VUMERITY may decrease lymphocyte counts. In the MS placebo5.1 Anaphylaxis and Angioedema controlled trials with dimethyl fumarate (which has the same active VUMERITY can cause anaphylaxis and angioedema after the first metabolite as VUMERITY), mean lymphocyte counts decreased by dose or at any time during treatment. Signs and symptoms in patients approximately 30% during the first year of treatment with dimethyl taking dimethyl fumarate (which has the same active metabolite as fumarate and then remained stable. Four weeks after stopping dimethyl VUMERITY) have included difficulty breathing, urticaria, and swelling fumarate, mean lymphocyte counts increased but did not return to of the throat and tongue. Patients should be instructed to discontinue baseline. Six percent (6%) of dimethyl fumarate patients and <1% of VUMERITY and seek immediate medical care should they experience placebo patients experienced lymphocyte counts <0.5 × 109/L (lower signs and symptoms of anaphylaxis or angioedema. limit of normal 0.91 × 109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with 5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred in dimethyl fumarate or placebo, respectively. There was no increased infections observed in patients with lymphocyte patients with MS treated with dimethyl fumarate (which has the same incidence of serious 9 9 active metabolite as VUMERITY). PML is an opportunistic viral infection counts <0.8 × 10 /L or ≤0.5 × 10 /L in controlled trials, although one
patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years) [see Warnings and Precautions (5.2)]. In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced lymphocyte counts <0.5 × 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 × 109/L with continued therapy. Neither VUMERITY® (diroximel fumarate) nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts. Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with VUMERITY, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of VUMERITY in patients with lymphocyte counts less than 0.5 × 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if VUMERITY is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution. Decisions about whether or not to restart VUMERITY should be individualized based on clinical circumstances.
The data described in the following sections were obtained using dimethyl fumarate delayed-release capsules, which has the same active metabolite as VUMERITY. Adverse Reactions in Placebo-Controlled Trials with Dimethyl Fumarate In the two well-controlled studies demonstrating effectiveness, 1529 patients received dimethyl fumarate with an overall exposure of 2244 person-years [see Clinical Studies (14)]. The adverse reactions presented in Table 1 below are based on safety information from 769 patients treated with dimethyl fumarate 240 mg twice a day and 771 placebo-treated patients. The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea. Table 1: Adverse Reactions in Study 1 and 2 Reported for Dimethyl Fumarate at ≥2% Higher Incidence than Placebo
Adverse Reactions
Dimethyl Fumarate 240 mg Twice Daily (N=769) %
Placebo (N=771)%
5.5 Liver Injury Clinically significant cases of liver injury have been reported in patients 40 6 treated with dimethyl fumarate (which has the same active metabolite Flushing as VUMERITY) in the postmarketing setting. The onset has ranged Abdominal pain 18 10 from a few days to several months after initiation of treatment with 14 11 dimethyl fumarate. Signs and symptoms of liver injury, including Diarrhea elevation of serum aminotransferases to greater than 5-fold the upper Nausea 12 9 limit of normal and elevation of total bilirubin to greater than 2-fold 9 5 the upper limit of normal have been observed. These abnormalities Vomiting resolved upon treatment discontinuation. Some cases required Pruritus 8 4 hospitalization. None of the reported cases resulted in liver failure, Rash 8 3 liver transplant, or death. However, the combination of new serum 6 4 aminotransferase elevations with increased levels of bilirubin caused Albumin urine present by drug-induced hepatocellular injury is an important predictor of Erythema 5 1 serious liver injury that may lead to acute liver failure, liver transplant, Dyspepsia 5 3 or death in some patients. Elevations of hepatic transaminases (most no greater than 3 times Aspartate aminotransferase 4 2 the upper limit of normal) were observed during controlled trials with increased dimethyl fumarate [see Adverse Reactions (6.1)]. Lymphopenia 2 <1 Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during Gastrointestinal treatment, as clinically indicated. Discontinue VUMERITY if clinically Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, significant liver injury induced by VUMERITY is suspected. abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and 5.6 Flushing VUMERITY may cause flushing (e.g., warmth, redness, itching, and/ usually decreased over time in patients treated with dimethyl fumarate or burning sensation). In clinical trials of dimethyl fumarate (which has compared with placebo. Four percent (4%) of patients treated with the same active metabolite as VUMERITY), 40% of dimethyl fumarate- dimethyl fumarate and less than 1% of placebo patients discontinued treated patients experienced flushing. Flushing symptoms generally due to gastrointestinal events. The incidence of serious GI events was began soon after initiating dimethyl fumarate and usually improved 1% in patients treated with dimethyl fumarate. or resolved over time. In the majority of patients who experienced Hepatic Transaminases flushing, it was mild or moderate in severity. Three percent (3%) of An increased incidence of elevations of hepatic transaminases in patients discontinued dimethyl fumarate for flushing and <1% had patients treated with dimethyl fumarate was seen primarily during serious flushing symptoms that were not life-threatening but led the first six months of treatment, and most patients with elevations to hospitalization. had levels <3 times the upper limit of normal (ULN) during controlled Administration of VUMERITY with food may reduce the incidence of trials. Elevations of alanine aminotransferase and aspartate flushing [see Dosage and Administration (2.3)]. Studies with dimethyl aminotransferase to ≥3 times the ULN occurred in a small number of fumarate show that administration of non-enteric coated aspirin (up to patients treated with both dimethyl fumarate and placebo and were a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence balanced between groups. There were no elevations in transaminases or severity of flushing [see Clinical Pharmacology (12.3)]. ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases 6. ADVERSE REACTIONS The following important adverse reactions are described elsewhere were <1% and were similar in patients treated with dimethyl fumarate or placebo. in labeling: • Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions Section (5.2)] • Herpes Zoster and Other Serious Opportunistic Infections [see Warnings and Precautions (5.3)] • Lymphopenia [see Warnings and Precautions (5.4)] • Liver Injury [see Warnings and Precautions (5.5)] • Flushing [see Warnings and Precautions (5.6)]
Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 months of therapy. Adverse Reactions in Clinical Studies with VUMERITY
In clinical studies assessing safety in patients with RRMS, approximately 700 patients were treated with VUMERITY and approximately 490 patients received more than 1 year of treatment with VUMERITY. The adverse reaction profile of VUMERITY was consistent 6.1 Clinical Trials Experience with the experience in the placebo-controlled clinical trials with Because clinical trials are conducted under widely varying conditions, dimethyl fumarate. adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval not reflect the rates observed in clinical practice.
use of dimethyl fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Liver function abnormalities (elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN) have been reported following dimethyl fumarate administration in post marketing experience [see Warnings and Precautions (5.5)]. Herpes zoster infection and other serious opportunistic infections have been reported with dimethyl fumarate administration in postmarketing experience [See Warnings and Precautions (5.3)]. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of VUMERITY® (diroximel fumarate) or dimethyl fumarate (which has the same active metabolite as VUMERITY) in pregnant women. In animal studies, administration of diroximel fumarate during pregnancy or throughout pregnancy and lactation resulted in adverse effects on embryofetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposures [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosage and Administration Inform patients that they will be provided a starter dose bottle: one capsule twice a day for the first 7 days and then two capsules twice a day thereafter. Advise patients to take VUMERITY as instructed. Inform patients to swallow VUMERITY capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that they should avoid a high-fat, high-calorie meal/snack at the time they take VUMERITY. If taken with food, the meal/snack should contain no more than 700 calories and no more than 30 g fat. Advise patients to avoid co-administration of VUMERITY with alcohol [see Dosage and Administration (2.2)]. Anaphylaxis and Angioedema Advise patients to discontinue VUMERITY and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.1)].
Progressive Multifocal Leukoencephalopathy Inform patients that progressive multifocal leukoencephalopathy (PML) has occured in patients who received dimethyl fumarate, and therefore may occur with VUMERITY. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Inform the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms Data associated with PML are diverse, progress over days to weeks, and Animal Data include progressive weakness on one side of the body or clumsiness Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/ of limbs, disturbance of vision, and changes in thinking, memory, day) to pregnant rats throughout organogenesis resulted in a decrease and orientation leading to confusion and personality changes [see in fetal body weight and an increase in fetal skeletal variations at the Warnings and Precautions (5.2)]. highest dose tested, which was associated with maternal toxicity. Plasma exposures (AUC) for MMF and HES (the major circulating drug- Herpes Zoster and Other Serious Opportunistic Infections related compound in humans) at the no-effect dose (100 mg/kg/day) Inform patients that herpes zoster and other serious opportunistic for adverse effects on embryofetal development were approximately infections have occurred in patients who received dimethyl fumarate 2 times those in humans at the recommended human dose (RHD) of and therefore may occur with VUMERITY. Instruct the patient of the importance of contacting their doctor if they develop any signs or 924 mg/day. Oral administration of diroximel fumarate (0, 50, 150, or 350 mg/kg/ symptoms associated with herpes zoster or other serious opportunistic day) to pregnant rabbits throughout organogenesis resulted in an infections [see Warnings and Precautions (5.3)]. increase in fetal skeletal malformations at the mid and high doses and Lymphocyte Counts reduced fetal body weight and increases in embryofetal death and Inform patients that VUMERITY may decrease lymphocyte counts. A fetal skeletal variations at the highest dose tested. The high dose was blood test should be obtained before they start therapy. Blood tests are associated with maternal toxicity. Plasma exposures (AUC) for MMF also recommended after 6 months of treatment, every 6 to 12 months and HES at the no-effect dose (50 mg/kg/day) for adverse effects on thereafter, and as clinically indicated [see Warnings and Precautions embryofetal development were similar to (MMF) or less than (HES) (5.4) and Adverse Reactions (6.1)]. those in humans at the RHD. Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/day) Liver Injury to rats throughout gestation and lactation resulted in reduced weight, Inform patients that VUMERITY may cause liver injury. Instruct which persisted into adulthood, and adverse effects on neurobehavioral patients treated with VUMERITY to report promptly to their healthcare function in offspring at the highest dose tested. Plasma exposures provider any symptoms that may indicate liver injury, including fatigue, (AUC) for MMF and HES at the no-effect dose for adverse effects on anorexia, right upper abdominal discomfort, dark urine, or jaundice. A postnatal development (100 mg/kg/day) were approximately 3 times blood test should be obtained before patients start therapy and during treatment, as clinically indicated [see Warnings and Precautions (5.5)]. (MMF) or similar to (HES) those in humans at the RHD. Flushing and Gastrointestinal (GI) Reactions 8.2 Lactation Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are Risk Summary There are no data on the presence of diroximel fumarate or metabolites the most common reactions, especially at the initiation of therapy, and (MMF, HES) in human milk. The effects on the breastfed infant and on may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI milk production are unknown. The developmental and health benefits of breastfeeding should be reactions. Advise patients experiencing flushing that taking VUMERITY considered along with the mother’s clinical need for VUMERITY and with food (avoid high-fat, high-calorie meal or snack) or taking a nonany potential adverse effects on the breastfed infant from the drug or enteric coated aspirin prior to taking VUMERITY may help [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. from the underlying maternal condition. Pregnancy 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been Instruct patients that if they are pregnant or plan to become pregnant while taking VUMERITY they should inform their healthcare provider established. [see Use in Specific Populations (8.1)]. 8.5 Geriatric Use Clinical studies of dimethyl fumarate and VUMERITY did not include 54499-02 sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Manufactured for: Biogen Inc. 8.6 Renal Impairment No dosage adjustment is necessary in patients with mild renal Cambridge, MA 02142 impairment. Because of an increase in the exposure of a major metabolite [2-hydroxyethyl succinimide (HES)], use of VUMERITY is VUMERITY is a registered trademark of Biogen. not recommended in patients with moderate or severe renal impairment © Biogen 2019 - 2020 [see Clinical Pharmacology (12.3)].
Conferences & Community
Missed the Advanced Practice Provider Education Series? Access It on Demand for Up to 12 Months! Even if you missed last month’s live, self-paced virtual education series designed especially for neurology advanced practice providers, you can still access all the overviews, updates, and resources on a variety of core topics in clinical neurology—at your convenience with Advanced Practice Provider Education Series On Demand. You’ll enjoy all the robust programming of the live event for up to 12 months, plus the chance to earn up to six CME credits.
AAN Advanced Practice Provider Neurology Education Series 2020
A Virtual Experience
Visit AAN.com/APP today to purchase yours and get ready to access: Six hours of online presentations Integrated online CME evaluations Curated library of Advanced Practice Provider resources Town Hall Forums featuring a panel of advanced practice providers and a Q&A session moderated by Calli Leighann Cook, DNP, FNP-C, FAANP, series co-director More
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Syllabi based on the ABPN Content Outline
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Conferences & Community
We’re Here for You—Renew for 2021 to Enjoy Robust Virtual Offerings, Strong Community continued from cover your community of peers, to help you do your job better and help advance the neurology profession through these unprecedented times. Unique online education opportunities to earn CME or continuous certification credits
AAN Member Services at memberservices@aan.com, (800) 879-1960, or (612) 928-6000 (international).
Exciting virtual networking events and opportunities Up-to-date information on breakthrough scientific research on the new Scientific Highlights platform Valuable clinical practice guidelines The latest news relevant to the profession Representation of your interests at the federal/state levels Special pricing on AAN products, services, or meetings Exclusive access to AAN.com member-only resources Find the full list of exclusive member benefits at AAN.com/benefits. For more information, contact
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Tools & Resources
2021 E/M Coding Changes Will Allow Providers to Focus on Patients, Not Paperwork continued from cover E/M CPT selection will be determined:
solely on the documented medical decision-making (MDM), OR the total time spent on the encounter (including non-face-to-face time) on the date of the encounter
The new guidance simply states, “The extent of history and physical examination is not an element in selection of office or other outpatient services.” The rule changes will permit providers to focus on medically relevant issues for the encounter and reduce the excessive documentation unrelated to the encounter previously needed to satisfy coding hoops. As part of the AMA CPT Editorial Panel’s revision of E/M guidelines, the Medical Decision Making (MDM) table has been revised as well. Every provider should personally review the new table, as the new format will likely be in use for some time. The basic structure is unchanged, retaining the following elements of medical decision making with nuanced changes (noted in bold): Number and complexity of problems addressed
It is up to the provider to use MDM as the basis for E/M selection, but the provider will be equally free to use total time spent on the day of the encounter instead. Counseling and/or coordination of care for the majority of the visit are no longer required to use time as the basis for E/M selection. The time does not have to be solely face-to-face to be counted. Some examples of non-patient-facing activities that count toward time spent on the date of the encounter are: Preparing to see a patient (e.g., reviewing tests) Ordering medications, tests, procedures Documenting clinical information in the electronic or other health record Independently interpreting results (not separately reported) and communicating results to the patient/family/caregiver Care coordination (not separately reported) The time associated with the different levels of outpatient service has changed slightly.
Amount and/or complexity of data to be reviewed and analyzed
New Patients
Established Patients
Risk of complications and/or morbidity or mortality of patient management.
( 99201 – deleted as of January 1, 2021)
9 9211 – physician not usually present*
9 9202 – 15–29 minutes
9 9212 – 10–19 minutes
99203 – 30–44 minutes
9 9213 – 20–29 minutes
9 9204 – 45–59 minutes
99214 – 30–39 minutes
9 9205 – 60-74 minutes
99215 – 40–54 minutes
E/M selection will still depend on the lower of any of two MDM categories selected. With the new table the guidance regarding selection within each of these categories has become more explicit.
* I f the physician’s time is spent in the supervision of clinical staff who perform the face-to-face services of the encounter, use 99211.
Overall, the changes should reduce the burden of unnecessary documentation and yet value the cognitive work performed by providers. Providers should remain attentive to appropriate and accurate ICD-10-CM coding to reflect the medical issues addressed and cognitive work performed with each encounter. With the expansive view of time in determining the E/M level, providers should also consider how they will document non-face-to-face time. The revision of the outpatient E/M code set is another step in the right direction of further recognition of cognitive care and the value of neurology. For answers to your questions about these E/M coding changes or other practice issues, visit AAN.com/EM or contact practice@aan.com.
Tools & Resources
New Axon Registry Measures Coming for 2021 The AAN's neurology-specific quality measurement sets are designed to help improve the care of your patients. They are integrated with the Academy’s Axon Registry ®—a free member benefit—to help members report for the Merit-based Incentive Payment System (MIPS). The Axon Registry will implement 10 quality measures in 2021. Axon 55: Comprehensive Epilepsy Care Center Referral or Discussion for Patients with Epilepsy Axon 56: Child: Neurodevelopmental/Neuropsychological Screening in Epilepsy Axon 57: DSP: Querying About Pain and Pain Interference with Function Axon 64: Patient Reported Falls and Plan of Care Axon 65: Fatigue Screening and Follow-up for Patients with MS Axon 66: Bladder, Bowel, or Sexual Dysfunction Screening and Follow-up for Patients with MS Axon 67: Migraine Preventive Therapy Management Axon 68: Acute Treatment Prescribed for Cluster Headache Axon 69: Preventive Treatment Prescribed for Cluster Headache Axon 70: Sleep Apnea: Assessment of Adherence to Positive Airway Pressure Therapy (QPP 279) AAN members should be aware of new quality measures available as qualified clinical data registry (QCDR) measures in the Axon Registry for 2021. QCDR measures are only available and implemented in registries designated as a QCDR like Axon Registry. The QCDR measures for 2021 are pending.
There are 10 returning QCDR measures for 2021. Axon 06.1: Querying About Symptoms of Autonomic Dysfunction for Patients with Parkinson’s Disease QCDR benchmark data available in 2020 for additional MIPS points Axon 11.1: Diabetes/Pre-diabetes Screening for Patients with DSP Axon 13: Medication Prescribed for Acute Migraine Attack QCDR benchmark data available in 2020 for additional MIPS points Axon 23: Exercise and Appropriate Physical Activity Counseling for Patients with MS QCDR benchmark data available in 2020 for additional MIPS points Axon 33.1: Querying for Co-morbid Conditions of Tic Disorder (TD) and Tourette Syndrome (TS) Axon 41: Quality of Life Assessment for Patients with Epilepsy Axon 44: Benign Positional Paroxysmal Vertigo (BPPV): Dix-Hallpike and Canalith Repositioning Axon 46: Pediatric Medication Reconciliation Axon 48: Activity Counseling for Back Pain Axon 54: Quality of Life for Patients with Neurologic Conditions The MIPS performance year starts on January 1 and ends on December 31 annually. Program participants using the Axon Registry must report the data collected during the 12-month calendar year by March 31 of the following year. For example, MIPS participants who collected data in 2020 via a QCDR must report their data by March 31, 2021, to be eligible for a payment increase and avoid a penalty in 2021. For more information on how to join the Axon Registry to meet your 2021 MIPS reporting and quality improvement needs, contact registry@aan.com.
24
AANnews • November 2020
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The American Brain Foundation was founded by the AAN as the premier foundation that promotes and invests in research across the whole spectrum of brain disease. With the help of AAN members, we continue our relentless pursuit of discovery research that will lead to improvements in diagnoses, treatments, and ultimately cures for brain diseases.
Renew your membership and donate today at AAN.com/membership
Tools & Resources
Headache Quality Measures Updated, Published in Neurology The AAN has published the Headache Quality Measurement Set, an update to the Academy’s 2013 measurement set, in the September 23, 2020, online issue of the Neurology ® journal and in the American Headache Society’s Headache: The Journal of Head and Face Pain. The AAN’s Headache Quality Measures Work Group created six measures on migraine and cluster headache and nine measures were retired. The measures are process measures, which quantify how often guidelines or protocols are adhered to. The AAN’s Axon Registry® has implemented the treatment for acute migraine attack measure. For more information on how to join the Axon Registry, contact registry@aan.com. The headache quality measurement set is available for free at AAN.com/policy-and-guidelines/ quality.
Neurology: Clinical Practice Covers Stroke, Neuropathy, Acute Flaccid Myelitis, and More The new issue of Neurology ® Clinical Practice offers readers an assortment of articles that will help them in their clinical work. The authors of “Outcomes of Interfacility Helicopter Transportation in Acute Stroke Care” discuss an important aspect of the care process of stroke patients with suspected large vessel occlusion which is the transportation method to the thrombectomy capable center. For “Quantitative Sensory Testing Predicts Histological Small Fiber Neuropathy in Postural Tachycardia Syndrome,” researchers conducted a retrospective study to investigate diagnostic procedures for patients with postural orthostatic tachycardia syndrome (POTS) and suspected small fiber neuropathy. This study showed diagnostic procedures with universal criteria should be developed by further examining pathophysiology and diagnostic procedures in POTS by randomized controlled trials. The study “Comparison of Children with Acute Flaccid Myelitis Before and After 2014” demonstrates clinical and imaging findings in response to treatment of children with AFM before and after 2014. 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.
Volume 10,
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A peer-revie
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RESEARCH
Synchronou s neurology –primary ca in a medical re collaborat home 388 ion RESEARCH
Cr yptogenic stroke: Cont emporar y tre treatments, nd and outcome s in the Unite s, d States 396 RESEARCH Novel and kn own morbidi tie identified us ing a phenom s of leukodystrophies e-wide assoc study 406 iation REVIEW
AANnews • November 2020
October 202
Neurolog
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Policy & Guidelines
Legislative Summit Advocates Urge Congressional Action on E/M, Telehealth The second annual AAN Legislative Summit took place on September 22 with 95 members from 47 states meeting with their Senate offices. All participants met with their senators' offices via video or conference call to urge Congress to support the implementation of the new payment structure for evaluation and management services as proposed in the 2021 Medicare Physician Fee Schedule. Advocates also expressed the AAN’s support for congressional efforts to expand telehealth access to patients throughout the COVID-19 public health emergency and make the improvements to telehealth use permanent.
Bruce H. Cohen, MD, FAAN, also discussed the E/M coding changes on a two-part Neurology MinuteTM Podcast in conjunction with the summit to help increase member awareness.
In addition, more than 300 members used the Advocacy Action Center to emphasize the same message on telehealth and E/M in emails to their senators.
Tyler Allison, MD; Lori Davis Noorollah, MD; and Sarah J. Hon, DO, FAAN
Sarah Song, MD, MPH, FAAN
Gurdesh Bedi, MD, FAAN; Sarah M. Benish, MD, FAAN; and Lyell K. Jones, MD, FAAN Korwyn Williams, MD, PhD, FAAN
Glen R. Finney, MD, FAAN
Kara Stavros, MD; Jonathan Cahill, MD, FAAN; and Sen. Jack Reed (D-RI) Aileen A. Antonio, MD; Thomas R. Vidic, MD, FAAN; and James F. Burke, MD
Policy & Guidelines
Three AAN Position Statements Updated in 2020 AAN policy requires all position documents to be reviewed every five years or earlier if the sponsoring committee believes an earlier review is warranted. The Advocacy Committee sponsored three position statement updates in 2020 including: Medical Cannabis Major changes included updating the terminology “medical marijuana” to “medical cannabis” and adding acknowledgement of FDA approval of pharmaceutical grade cannabidiol (CBD) to treat some forms of epilepsy. Sports Concussion: Policy Implications The statement required an update since all 50 states and the District of Columbia have enacted legislation regarding sports concussion following the publication of the original position statement. As a result of legislative progress, the author group updated the language to more broadly focus on policy which could apply at any level of government or institution. The author group also added language pertaining to return to learn considerations. Stroke Care Significant revisions were made to reflect new advancements in stroke care. The author group incorporated qualifications for comprehensive stroke and thrombectomy-capable stroke centers DEP: YY(Projectcenters Name) Ad—Half Page Horizontal> AN Placed in AANnews and designated a separate section for emergency 8.25 x 5.25 +0.125 bleed, 4C
medical services. They also added new sections on quality improvement and rehabilitation. There were also substantial edits to the telestroke section to reflect the use of IV tPA, as well as an acknowledgement of the changing telehealth landscape due to COVID-19. Read all the AAN position statements at AAN.com/policy-andguidelines/policy/position-statements/. POSITION STATEMENT:
USE OF MEDICAL CANNABIS FOR NEUROLOGIC DISORDERS
BACKGROUND
POSITION STATEMENT:
SPORTS CONCUSSION
The American Academy of Neurology (AAN) is a professional organization of over 36,000 practicing neurologists and neuroscientists with a deep and abiding interest in assuring the best possible care of patients with all types of neurologic disorders.
Background
Legislation has been passed in 33 states and the District of Columbia for the use of cannabis for medical purposes, POSITION STATEMENT: which protects users from criminal penalties, allows access to a variety of products and strains, and enables The American Neurology (AAN)—an (CBD) association of more smoking or vaporizing of products. Separately, 13 states allow for Academy the use ofofmedical cannabidiol products or than 36,000 neurologists and neuroscience professionals dedicated to providing the best1 possible care for patients with neurologic disorders—advocates for policy measures that tetrahydrocannabinol (THC) products for medical purposes in limited situations. Most of these state laws include promote high quality, safe care of individuals participating in sport and other physical activities. Neurologists specialize in specific provisions for individuals living with neurologic conditions likeofintractable (treatment resistant) epilepsy, treating disorders the brain and nervous system. Some neurologists have particular interest and experience caring for multiple sclerosis, ALS, and Parkinson’s disease. Asathlete these brain policies are Although adopted and expanded, it is vitally important health. neurologists broadly recognize the healthThe benefits of participation we are(AAN)—an also uniquely American Academyinofsports, Neurology association of more than 36,000 neurologists and neuroscience qualified to manage with a variety ofand neurologic injuries and disorders, including sports-related concussion. for the AAN to have an official position on the issue that can inform andathletes assist policymakers practitioners. professionals dedicated to providing the best possible care for patients with neurologic disorders—is an advocate for policy measures that promote high quality, safe, and cost-effective stroke care.
DESCRIPTION OF THE ISSUE
STROKE CARE
Description of Issue
Stroke is the nation’s fifth leading cause of death and a leading cause of adult long-term disability. According to the Concussion a form of mildnot traumatic brain injury (TBI) resulting from American a direct or indirect impact to the head body, and is Stroke Association, aboutor795,000 people suffer a new or recurrent stroke each year, with 142,000 not In this position statement updated from 2014 and 2018, the AANisrecommends using the phrase “medical a common consequence of sport participation. An estimated 1.6 to 3.8 million sports-related concussions occur in the United marijuana” but rather the use of “cannabis for medical purposes” for clarity and to specifically delineate that not all surviving. Acute stroke care is complex, multilayered, and involves many parts of the health care system. Stroke States each year.1 While concussions themselves are usually self-limited injuries, they may be associated with catastrophic prevention, care, and outcomes can be improved through a comprehensive stroke system of care. Policymakers phytocannabinoids may be useful in neurologic conditions. injuries such as spinal cord injury and skull fracture. Additionally, long-term effects of repetitive head impact exposures without great responsibility and impact onincreased such systems, and they need to take an active role in improving stroke care. associated clinical manifestations of concussion are unknown. A historyhave of prior concussion is associated with an risk 2 Existing limited medical research does not support the present and proposed legislative policies across the country This includes supporting the implementation of primary stroke centers in both urban and rural communities, access for recurrent concussions. that promote cannabis-based products as treatmentThe options for the majority of neurologic disorders.2 Most studies to advanced stroke centers with multiple endovascular and surgical capabilities, endorsement of telestroke as a proven effect of concussion on developing brains is of particular concern. Children with concussion, particularly concussions, are small and inadequately designed. There are concerns regarding the composition of cannabis purportedly for wayimpaired to deliver acute stroke consultation, proper reimbursement for on-call consultations, and use of advanced are at risk for developing chronic or recurring headaches and suffering from memory, cognitive dysfunction, attention 2 medical use as well as the consistency of quality control assurance measures used in production. There are deficitand disorders, and other behavioral changes. Symptoms of neurologic and neuro-behavioral disorders such as depression, technological services. 3 stress disorder, anxiety, sleep disorder, vestibular and dysfunction, cervicalgia and oculomotor dysfunction may also be also concerns regarding the safety of using cannabispost-traumatic in medical settings, especially for pediatric patients 4 experienced uptreat to six neurologic months following a concussion. Unfortunately, an estimated 283,000 children visit emergency departments Psychiatric and people with disorders of the nervous system who use cannabis to diseases. year toof seek care for sportsand recreation-related TBIs,be including concussions.3 Among high school students, 15.1 percent neurocognitive adverse effects have been described each in studies recreational and medical use,5 which may report having at least one concussion related to sports or physical activity.4 particularly problematic in a population with compromised neurologic function. The interaction of these compounds The Academy supports the development and expansion of community, statewide, and regional networks of stroke All fifty states and the District of Columbia have legislation aimed at protecting our nation’s youth from potential with prescription medications is uncertain and may introduce unnecessary and unknown risk forenacted patients living with centers, as these will improve the availability and quality of stroke care to those who live in all areas. Hospitals that serious negative outcomes related6 to sport-related concussion. Most legislation requires education about concussion, removal chronic, complex neurologic diseases that require one or more prescription drugs. In addition, inconsistency and lack neurologic or radiologic personnel should establish relationships with primary or advanced stroke centers for from play for at least 24 hours in the event of a suspected concussion, and return to play only after evaluation by a qualified inaccurate labeling exists for the products that are outside the provider purviewand of the Food & Drug Administration (FDA). rapid assessment and transfer as needed. healthcare a described return-to-play protocol.
Stroke Center Designation
The AAN strongly encourages statecannabidiol and local policymakers to update policies and regulations to ensure youth with Studies do support the use of the FDA-approved plant-based pharmaceutical grade (CBD) product that relevant The Academy encourages policymakers to consider the following when determining qualifications for a primary sports-related concussions receive appropriate care. can be legally prescribed in all 50 states without need for a special Drug Enforcement Agency (DEA) license to treat stroke center (PSC): seizures associated with Lennox-Gastaut syndrome (LGS)7 and Dravet syndrome8 for patients two years and older, • At least one neurologist should play a key role in the development and/or designation of primary stroke centers. and tuberous sclerosis complex (TSC) for patients one year and older. include mandating that a neurologist be appointed to any primary stroke center task force, panel, or Concussion policies across levels of government and organizations shouldThis aim should for: More quality and thorough research in other areas outside of epilepsy is urgently needed to determine the safety and committee which policymakers might develop. • Pre-participation Concussion Education to Student-athletes potential medical benefit of various forms of cannabis forThe neurologic disorders, especially those for which anecdotal AAN supports strong educational resources such as the Centers Disease Control andDirector, Prevention’s Heads Up: • A for single Stroke Medical preferably a neurologist, ideally with vascular neurology fellowship training, evidence is available but where strong scientific data is lacking. Anecdotal maytraining engender public Concussion in Youth evidence Sports online course forsupport coaches and parents.5 Processes to confirm that both parent should be appointed, with authority and accountability for the operation of the hospital-based stroke program. for the use of cannabis to treat neurologic diseases, but or such information must be supported and substantiated bythe educational information, and consent to participate legal guardian and athlete have received and understand This Stroke Medical Director is charged with ensuring the quality of stroke care delivery and earning and should be considered. rigorous research, which can then inform government policy. maintaining certification as indicated. The Stroke Medical Director should be adequately reimbursed for their • Removal from Play time and substantial efforts in carrying out those responsibilities.
Concussion Policy for Youth and High School Sports
The AAN supports removal from participation for any athlete who is exhibiting symptoms or signs of a concussion until they are evaluated by a qualified healthcare provider properly trained•inAll thehospitals assessment and management of have concussion, should be required to a plan for the management of acute stroke patients that is written, easily such as a neurologist and as defined by state law. This includes sports recognized high school athletic associations as include rapid imaging and identification of patients with large accessible,byand updated regularly. Plans should well as youth and recreational leagues, and other organizations that oversee organized sport.
vessel occlusion who may benefit from rapid transfer to a comprehensive stroke center (CSC) or thrombectomy-
Page 1 of 3 capable stroke center (TSC).
POSITION STATEMENT: Use of Medical Cannabis for Neurologic Disorders
• When considering requirements for transporting patients to a primary stroke center, prerequisites for emergency personnel decision-making should include knowledge of which hospitals can provide intravenous thrombolytic therapy within 4.5 hours of ischemic stroke onset and the capacity to care for these patients postthrombolysis. These capabilities should be available on a 24/7 basis. POSITION STATEMENT:: Sports Concussion
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• Reciprocal transfer commitments are a feasible mechanism to ensure patient access to stroke care and subsequent return to their communities.
POSITION STATEMENT:Stroke Care
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#NeurologyProud and proud to call the AAN my home. Share why you are #NeurologyProud on social media.
Christina Kelly Vest, NP
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.
Recommendations Made to Support Fee Schedule Changes On September 23, the AAN submitted comments to the Centers for Medicare & Medicaid Services (CMS) in response to the 2021 Medicare Physician Fee Schedule Proposed Rule. In 2021, CMS expects payments across the specialty of neurology to increase by six percent with variations depending on the individual provider’s practice. The AAN’s comments urged the agency to move forward with its planned implementation of a new coding and payment structure for evaluation and management services (E/M), without modification or delay, and offered a number of recommendations to the agency on key provisions of the agency’s E/M policies. The AAN also submitted robust comments on the telehealth provisions of the proposed rule, recommending that the agency permanently implement changes to promote expanded access to telehealth services. Specifically, the AAN calls on the agency to permanently add a number of services to the Medicare telehealth list, provide coverage for audio-only telephone E/M services, ease restrictions on other communication technology-based services, and make modifications to several other restrictions on the provision of telehealth services. The comments also provide the agency with experiential feedback from neurologists from across the country on the use of telehealth services both before and during the COVID-19 public health emergency and provide an overview of the developing literature surrounding the benefits of telehealth. The comments also addressed other key changes including annual updates to the Quality Payment program. You can read a recent op-ed by AAN President James C. Stevens, MD, FAAN, on the importance of the E/M changes at medpagetoday.com/practicemanagement/reimbursement/88974.
Academy Raises Opposition to Expansion of PA Requirements Additionally, on October 1, the AAN submitted comments in response to the 2021 Hospital Outpatient Prospective Payment System proposed rule. The comments oppose a recent expansion of prior authorization (PA) requirements for botulinum toxin
injections within the Medicare program. The AAN’s comments also offered recommendations for alternative solutions that do not impose burdensome PA requirements on providers. The AAN has previously met with CMS to raise our concerns with the new requirements and offer evidence contradicting the need for additional PAs.
Other Advocacy Updates President Trump signed into law a continuing resolution (CR) which extends FY 2020 government funding levels through December 11. The CR does not include additional funds for NIH but does include language allowing NIH to provide no-cost extensions to specific grants available for obligation through FY 2015 and set to expire on September 30, 2020. The CR also extends the deadline to repay loans from the Medicare Advance and Accelerated Payments program. The AAN continues to advocate for neurology research funding priorities for FY 2021. The AAN joined an open letter led by the Alliance for Aging Research urging federal health care agencies to prioritize science over politics in response to COVID-19. The AAN also joined a letter led by the Infectious Diseases Society of America to the FDA regarding COVID-19 vaccine safety. The House Oversight and Government Reform Committee continued its 18-month drug pricing probe with two days of hearings including testimony from six large pharmaceutical companies. Teva’s multiple sclerosis therapy, Copaxone, and Mallinckrodt’s recently acquired inflammation drug, ActharGel, were targeted for their rapidly increasing prices and the connection to higher revenue levels in recent years. The AAN continues to follow the drug pricing battle on Capitol Hill and advocate for patient access to lifesaving therapies that should not be negatively impacted by the exorbitant cost of drugs.
AANnews • November 2020 29
Education & Research
AAN Releases Recommendations for 2020–2021 Virtual Interview Season In response to the impacts of the COVID-19 pandemic on medical schools and residency programs, the Coalition for Physician Accountability (CoPA)—a coalition of more than a dozen organizations, including the American Medical Association, Accreditation Council for Graduate Medical Education, Accreditation Council for Continuing Medical Education, Association of American Medical Colleges, and others—released in May recommendations to support all aspects of the virtual interview process, including away rotations, recruitment, and application review. Realizing a need for resources to support students during the anticipated virtual interview season, the AAN subsequently sought input from medical students, clerkship directors, and program directors via a survey designed to better understand their needs in relation to the anticipated virtual interview process. Recognizing that some areas are disproportionately affected by COVID-19 and applicants have been disproportionately impacted by the health and financial ramifications of the pandemic, data from the survey was used to develop recommendations to support all involved with the virtual interview process, and maximize safety and equity for both applicants and neurology and child neurology programs. The AAN recommendations are as follows: 1. Away rotations (CoPA recommendation 1) a. A way rotations should not be mandatory. b. A way rotations should be limited to students who cannot get a similar/comparable experience at their home institution. c. C onsider engagement in virtual experiences such as virtual visiting clerkships and other online educational programming. 2. Virtual Recruitment/Interviews (CoPA recommendation 2) a. C ommit to online interviews and virtual visits for all the applicants, including local students, in place of in-person interviews for the entire cycle. This is both to minimize health risks from traveling and to provide an equitable platform for applicants and programs. b. C reate a robust virtual environment and share virtual interview best practices with applicants, faculty, and residents to streamline and optimize the interview experience.
c. A ctively work to attract and recruit applicants from diverse backgrounds, including traditionally underrepresented groups, to enhance the diversity among neurology trainees to better represent and meet the needs of the populations we serve. d. U tilize alternative platforms to ensure that all applicants have equal access to participate in virtual recruitment and interviews. 3. Application Review a. C omplete/maintain a holistic review of applications, recognizing that access to different clinical, research, extracurricular, work, and other experiences vary significantly in normal circumstances and are further impacted by the COVID-19 pandemic. b. Recognize that a significant proportion of medical students will have completed their clerkship training in a non-traditional environment during the pandemic with exclusively virtual learning experiences and on-line educational programming. Some clerkships may have transitioned to pass/fail grading in this setting. c. H ave flexibility with requirement of neurologyspecific letters of recommendation for screening, acknowledging that applicants may not have had access to neurology rotations prior to applying. d. D o not require that a sub-I be completed by the time of the initial application review. e. D ue to limited testing site availability as a result of COVID-19, be aware that Step 2CK and/or Step 2CS may not be completed.
To read the full CoPA Consensus Statement or learn more about the AAN’s recommendations, visit AAN.com/2020Consensus. For a list of virtual interview tips for students, visit AAN.com/2020Virtual. 30
AANnews • November 2020
April 17 – April 22 • San Francisco In-person and Virtual
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Education & Research
ABPN Pilot Project Approved as Permanent Alternative to 10-year MOC Examination The American Board of Medical Specialties (ABMS) has approved a successful pilot project by the American Board of Psychiatry and Neurology (ABPN) as a permanent alternative to the secure, proctored 10-year Continuing Certification (CC/MOC) examination. The new Article Assessment Pathway will be offered beginning with the 2022 assessments and exams, including ABPNadministered subspecialties. "This is great news for ABPN diplomates,” said AAN CEO Mary Post, MBA, CAE. “The new pathway will offer greater flexibility for meeting CC/MOC Part II program requirements.” Look for more details to be available on the ABPN website in the coming months at ABPN.com.
New NeuroReady Now Available for Advanced Practice Providers If you’re an advanced practice provider one to three years out of graduation and looking for a solid foundational knowledge in neurology, then the AAN’s newest online resource for care team members is for you! The NeuroReady: Advanced Practice Provider Edition offers a convenient online format that includes 12 months of access and is designed specifically to help care team members: Identify areas of neurology that require more focused study and review Self-assess knowledge after completion of the educational program to further focus study and review Demonstrate improved competency and performance in clinical neurology
Visit AAN.com/NeuroReadyAPP to get started.
32
AANnews • November 2020
Additional features include: Syllabi on eight categories in clinical neurology Condensed audio interviews with neurology professionals for review online, or downloadable for on-the-go listening Over 160 multiple-choice question self-assessment exam with feedback by subspecialty areas and suggestions for further reading and comparative peer performance results
Advanced Practice Provider Edition
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Stroke Neurologist, Department of Neurology—NYU Langone Health Brooklyn, New York The Department of Neurology at NYU Langone Health in Brooklyn, NY is recruiting a faculty member with a primary interest in clinical stroke. Candidates must be board eligible/certified in Neurology and have completed fellowship training in this sub-specialty. Clinical research experience is desirable. Strong leadership skills and a commitment to excellence in teaching are required. The rank and track will depend on the qualifications of the candidate. Individuals interested in this position should send a letter of interest, current CV, and the names of three references to: Steven L. Galetta, MD, Chair of Neurology, NYU Langone Health, 222 East 41st Street, 14th Floor, New York, NY 10017; Email: Jaclyn.Bonello@nyulangone.org. NYU Langone Health is an affirmative action equal opportunity employer and strongly encourages applications from women and underrepresented minorities. AANnews® Classified Advertising he AAN offers a complete package of print, online, and in-person T recruitment advertising opportunities. Visit Careers.AAN.com for all AAN options, rates, and deadlines. d copy for the January 2021 print edition of AANnews must be submitted A by December 1, 2020. The same deadline applies to changes/cancellations. he American Academy of Neurology reserves the right to decline, T withdraw, or edit advertisements at its discretion. Every care is taken to avoid mistakes, but the responsibility for clerical or printer errors does not exceed the cost of the ad.
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AANnews • November 2020
GOCOVRI® (amantadine) extended release capsules Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. INDICATIONS AND USAGE: GOCOVRI is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications. CONTRAINDICATIONS: Contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2 WARNINGS AND PRECAUTIONS: Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported in 4% vs 1% of patients treated with GOCOVRI or placebo, respectively. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (eg, driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence. Suicidality and Depression: In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% vs 0%; depression or depressed mood 6% vs 1%; confusional state 3% vs 2%; apathy 2% vs 0%, of patients treated with GOCOVRI or placebo, respectively. Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression. Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucination, auditory hallucination, delusions, illusions, or paranoia was 25% vs 3%; hallucinations caused discontinuation of treatment in 8% vs 0%; of patients treated with GOCOVRI or placebo, respectively. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases. Dizziness and Orthostatic Hypotension: In controlled clinical trials, 29% vs 2% experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension; and 3% vs 0% discontinued study treatment because of dizziness, postural dizziness, or syncope; of patients receiving GOCOVRI or placebo, respectively. Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol with GOCOVRI is not recommended. Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. If possible, avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of such urges, and to consider dose reduction or stopping GOCOVRI treatment. ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. GOCOVRI was evaluated in 2 double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients). The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for 1 week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Study 1 was stopped prematurely unrelated to safety, with 39/100 patients (safety population) treated with GOCOVRI for 24 weeks. The most common adverse reactions reported in >10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. The overall rate of discontinuation because of adverse reactions was 20% vs 8% for patients treated with GOCOVRI or placebo, respectively. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucination (8% GOCOVRI vs 0% placebo), dry mouth (3% GOCOVRI vs 0% placebo), peripheral edema (3% GOCOVRI vs 0% placebo), blurred vision (3% GOCOVRI vs 0% placebo), postural dizziness and syncope (2% GOCOVRI vs 0% placebo), abnormal dreams (2% GOCOVRI vs 1% placebo), dysphagia (2% GOCOVRI vs 0% placebo), and gait disturbance (2% GOCOVRI vs 0% placebo). Pooled Analysis of Adverse Reactions Reported for ≥3% of Patients Treated With GOCOVRI 274 mg (n=100) or placebo (n=98), respectively: Psychiatric disorders: visual and/or auditory hallucination (21%, 3%); anxiety and/or generalized anxiety (7%, 3%); insomnia (7%, 2%); depression/depressed mood (6%, 1%); abnormal dreams (4%, 2%); confusional state (3%, 2%) Nervous system disorders: dizziness (16%, 1%); headache (6%, 4%); dystonia (3%, 1%) Gastrointestinal disorders: dry mouth (16%, 1%); constipation (13%, 3%); nausea (8%, 3%); vomiting (3%, 0%) General disorders and administration-site conditions: peripheral edema (16%, 1%); gait disturbance (3%, 0%) Injury, poisoning, and procedural complications: fall (13%, 7%); contusion (6%, 1%) Infections and infestations: urinary tract infection (10%, 5%) Skin and subcutaneous tissue disorders: livedo reticularis (6%, 0%); pigmentation disorder (3%, 0%) Metabolism and nutrition disorders: decreased appetite (6%, 1%) Vascular disorders: orthostatic hypotension, including postural dizziness, syncope, presyncope, and hypotension (13%, 1%) Eye disorders: blurred vision (4%, 1%); cataract (3%, 1%); dry eye (3%, 0%) Musculoskeletal and connective tissue disorders: joint swelling (3%, 0%), muscle spasm (3%, 0%) Reproductive system and breast disorders: benign prostatic
hyperplasia—all male (6%, 2%) Respiratory, thoracic, and mediastinal disorders: cough (3%, 0%). Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia. Difference in the Frequency of Adverse Reactions by Gender in Patients Treated With GOCOVRI Adverse reactions reported more frequently in women (n=46) vs men (n=54) were: dry mouth (22% vs 11%), nausea (13% vs 4%), livedo reticularis (13% vs 0%), abnormal dreams (9% vs 0%), and cataracts (7% vs 0%), respectively. Men vs women reported the following adverse reactions more frequently: dizziness (20% vs 11%), peripheral edema (19% vs 11%), anxiety (11% vs 2%), orthostatic hypotension (7% vs 2%), and gait disturbance (6% vs 0%), respectively. Difference in the Frequency of Adverse Reactions by Age in Patients Treated With GOCOVRI Hallucinations (visual or auditory) were reported in 31% of patients age 65 years and over (n=52) vs 10 % in patients below the age of 65 years (n=48). Falls were reported in 17% of patients age 65 and over vs 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over compared with 2% of patients below age 65. DRUG INTERACTIONS: Other Anticholinergic Drugs: Products with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. The dose of anticholinergic drugs or of GOCOVRI should be reduced if atropine-like effects appear when these drugs are used concurrently. Drugs Affecting Urinary pH: The pH of the urine has been reported to influence the excretion rate of amantadine. Urine pH is altered by diet, drugs (eg, carbonic anhydrase inhibitors, sodium bicarbonate), and clinical state of the patient (eg, renal tubular acidosis or severe infections of the urinary tract). Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. Alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively. Live Attenuated Influenza Vaccines: Due to its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live vaccines are not recommended during treatment with GOCOVRI. Inactivated influenza vaccines may be used, as appropriate. Alcohol: Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension, and may result in dose-dumping. USE IN SPECIFIC POPULATIONS: Pregnancy: There are no adequate data on the developmental risk associated with use of amantadine in pregnant women. Based on animal data, it may cause fetal harm. Lactation: Amantadine is excreted into human milk, but amounts have not been quantified. There is no information on the risk to a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GOCOVRI and any potential adverse effects on the breastfed infant from GOCOVRI or from the underlying maternal condition. Pediatric Use: Safety and effectiveness of GOCOVRI in pediatric patients have not been established. Geriatric Use: In Phase 3 clinical trials, the mean age of patients at study entry was 65 years. Of the total number of patients in clinical studies of GOCOVRI, 46% were less than 65 years of age, 39% were 65-74 years of age, and 15% were 75 years of age or older. Hallucinations and falls occurred more frequently in patients 65 years of age or older, compared with those less than 65 years of age. No dose adjustment is recommended on the basis of age. GOCOVRI is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Renal Impairment: GOCOVRI is contraindicated for use in patients with end-stage renal disease (creatinine clearance values lower than 15 mL/min/1.73 m2). A 50% dose reduction of GOCOVRI to a starting daily dose of 68.5 mg daily for a week, followed by a daily maintenance dose of 137 mg is recommended in patients with moderate renal impairment (creatinine clearance between 30 and 59 mL/min/1.73 m2). For patients with severe renal impairment (creatinine clearance between 15 and 29 mL/min/1.73 m2), a daily dose of 68.5 mg is recommended. Overdosage: Deaths have been reported from overdose with amantadine immediaterelease. The lowest reported acute lethal dose was 1 g of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction, including increased BUN and decreased creatinine clearance, can occur. Central nervous system effects that have been reported with overdose include agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor, disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has occurred with amantadine overdose. For acute overdosing, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary. The excretion rate of amantadine increases with acidification of urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes. Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias. Monitor blood electrolytes, urine pH, and urinary output. Although amantadine is not efficiently removed by hemodialysis, this procedure may be useful in the treatment of amantadine toxicity in patients with renal failure. References: 1. GOCOVRI® (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2020. 2. Hauser RA, Pahwa R, Wargin WA, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77-88. 3. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS- 5102 (amantadine) extended-release capsules for dyskinesia in Parkinson disease. CNS Drugs. 2018;32(4): 387-398. 4. Data on file. Adamas Pharma LLC, Emeryville, CA.
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NIGHTTIME DOSING DOSING NIGHTTIME
DAYTIMEDAYTIME COVERAGE COVERAGE
For Parkinson's disease patients with motor complications,1,2
GOCOVRI® COULD MEAN THE DIFFERENCE
BETWEEN GETTING UP
AND GETTING OUT GOCOVRI® is ready when your Parkinson’s disease (PD) patients with dyskinesia need it 2 With a single bedtime dose, high levels of GOCOVRI® are reached by morning before the first levodopa dose, providing all-day coverage with levels slowly decreasing in the hours before bedtime.2 In clinical trials, GOCOVRI® reduced PD dyskinesia (primary endpoint) and OFF time and increased GOOD ON time (secondary endpoints).1 *
Not an actual patient.
31% DECREASE IN DYSKINESIA 36% DECREASE IN OFF TIME 29% INCREASE IN GOOD ON TIME
10.1-point reduction in UDysRS score (-17.7 GOCOVRI® vs -7.6 placebo) 3,4†
1-hour decrease (-0.6 GOCOVRI® vs 0.4 placebo) 3,4†
2.4-hour increase (3.8 GOCOVRI® vs 1.4 placebo) 3,4†
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GOOD ON time, ON time without troublesome dyskinesia; UDysRS, Unified Dyskinesia Rating Scale.
*As seen in pooled results of 2 independently positive, pivotal, Phase 3, randomized, placebo-controlled trials (Study 1 and Study 2) in PD patients on levodopa. Study 1, a 24-week study, was conducted in 121 PD patients with dyskinesia (GOCOVRI® [n = 63], placebo [n = 58]). Study 2, a 12-week study, was conducted in 75 PD patients with dyskinesia (GOCOVRI® [n = 37], placebo [n = 38]).1,3 † In Study 1, GOCOVRI® reduced the UDysRS total score by 15.9 points (vs 8.0 with placebo) (P = 0.0009), decreased OFF time by 0.6 hours (vs an increase of 0.3 hours with placebo) (P = 0.0171), and increased GOOD ON time by 3.6 hours (vs 0.8 hours with placebo) (P < 0.0001) from baseline. In Study 2, GOCOVRI® reduced the UDysRS total score by 20.7 points (vs 6.3 with placebo) (P < 0.0001), decreased OFF time by 0.5 hours (vs an increase of 0.6 hours with placebo) (P = 0.0199), and increased GOOD ON time by 4.0 hours (vs 2.1 hours with placebo) (P = 0.0168) from baseline.1
INDICATION GOCOVRI® (amantadine) extended release capsules is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopabased therapy, with or without concomitant dopaminergic medications. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2. WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities. Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.
Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases. Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI. Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or stopping medications. ADVERSE REACTIONS The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.
Please see Brief Summary of full Prescribing Information on the adjacent page.
Adamas and Gocovri are registered trademarks of Adamas Pharmaceuticals, Inc. or its related companies. © 2020 Adamas Pharmaceuticals, Inc. or its related companies. All rights reserved. GOC-0728 09/20