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A CSPE Core Curriculum Series

102

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MS-102: Navigating the MS Therapeutic Landscape

Digital Guide Book

Multiple sclerosis (MS) affects an estimated 400,000 people in the U.S., with approximately 10,000 new cases reported every year. As a chronic and progressive neurologic disease that requires lifelong, dynamic treatment via costly, high-touch medications that also require special handling and storage, multiple sclerosis therapies are often delivered via specialty pharmacy programs. The NASP/CSPE MS Core Curriculum Series is intended to increase specialty clinicians’ knowledge of the evolving MS treatment paradigm and provide the necessary professional education to counsel patients and caregivers on the myriad therapeutic options, routes of administration, and behavioral/clinical/financial variables that must be considered alongside drug therapy choices when treating MS across care settings. As the second installment in the four-module NASP/CSPE MS Core Curriculum Series, this activity provides an in-depth discussion of the various therapies used in the treatment of MS.

Learning Objectives

The target audience for this activity includes pharmacists and nurses caring for MS patients. Upon completion of this activity, the participant will be able to: Differentiate the “platform” Disease-Modifying Therapies (DMTs) and newer oral and injectable Multiple Sclerosis (MS)

therapies with regard to efficacy, safety and tolerability, and immunological activity. Recognize how the product is supplied and how to properly administer as well as store each disease-modifying therapy. Outline the latest evidence-based therapeutic regimens for relapsing MS, including staging, sequencing, and combination

treatment across care settings.

Faculty

Aimee M. Banks, Pharm D, BCPS

Clinical Pharmacist Vanderbilt University Medical Center Multiple Sclerosis Clinic Nashville, Tennessee

Brandon M. Markley, Pharm D, BCPS

Clinical Pharmacist Vanderbilt University Medical Center Multiple Sclerosis Clinic Nashville, Tennessee

Steering Review Committee

Susan Allen, PharmD, Amber Pharmacy Aimee Banks, PharmD, Specialty Pharmacy Service, Vanderbilt Medical Center Joy Derwenskus, DO, MS, Advanced Neurosciences Institute Stephanie LaPointe, PharmD, Diplomat Specialty Pharmacy Brandon Markley, PharmD, Vanderbilt University Medical Center Mel Nelson, PharmD, Fairview Specialty Pharmacy Stacey Ness, PharmD, Managed Health Care Associates Libin Philip, PharmD, Diplomat Specialty Pharmacy

This activity is supported by educational grants from Bayer, Genzyme, a Sanofi Company, and Novartis.

The material presented in this CE activity does not reflect the views of ProCE, Inc. or the commercial sponsor. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

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Accreditation This CE activity is jointly provided by ProCE, Inc. and the National Association of Specialty Pharmacy (NASP). ProCE is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221-9999-16-321-H01-P has been assigned to this knowledge-based, home-study activity. This CE activity is approved for 1.0 contact hour (0.1 CEU) in states that recognize ACPE providers, and is provided at no cost to participants. Completion of an evaluation and post-test with a score of 70% or higher is required to receive CE credit. Proof of completion will be posted in NABP CPE Monitor profiles. No partial credit will be given.

Release Date: 11-02-2016 Expiration Date: 11-02-2019

This CE activity is jointly provided by ProCE, Inc. and Wild Iris Medical Education, Inc. This activity provides 1.0 contact hour of nurse CE credit. Wild Iris Medical Education, Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

About the Faculty Brandon Markley, Pharm D, BCPS Dr. Markley received his Bachelor of Science degree in Pharmaceutical Sciences in 2007 and his Doctor of Pharmacy degree in 2009 from South Dakota State University in Brookings, SD. He went on to complete an ASHP-accredited pharmacy practice residency at the Veterans Affairs Medical Center in Nashville, TN. Upon completion of his residency training in 2010, Dr. Markley accepted a position at University Medical Center and Roseman University of Health Sciences College of Pharmacy in Las Vegas, NV as a Clinical Pharmacy Specialist and Assistant Professor of Pharmacy Practice. While in Las Vegas, Dr. Markley also served as a clinical professor with the University of Nevada School of Medicine. Following his return to Nashville in 2013, Dr. Markley initially accepted a position at Ft Campbell Army Community Hospital as a Clinical Pharmacist

working under a physician-directed collaborative practice agreement, before transitioning to Vanderbilt University Medical Center where he currently works as a Clinical Pharmacist in the Vanderbilt Multiple Sclerosis Clinic. Dr. Markley, who is Board Certified as a Pharmacotherapy Specialist (BCPS), has publications in the following journals: Journal of Nephrology, Southern Medical Journal, and American Journal of Medical Sciences.

Aimee Banks, PharmD, BCPS Aimee Banks PharmD, BCPS, is a graduate of the University of Tennessee College of Pharmacy in Memphis, Tennessee. After graduation, she completed a PGY-1 pharmacy practice residency at the Veterans Affairs Medical Center in Memphis and became Board Certified as a Pharmacotherapy Specialist (BCPS). Upon joining the Vanderbilt Specialty Pharmacy team, Aimee piloted specialty pharmacy services in the Vanderbilt Multiple Sclerosis (MS) Center, where she continues to serve patients and manage their specialty pharmacy needs. As a pharmacist embedded in the MS clinic, Aimee has a unique opportunity to provide comprehensive and coordinated specialty pharmacy care for Vanderbilt MS patients.

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Faculty Disclosures It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Aimee Banks and Brandon Markley have no relevant commercial and/or financial relationships to disclose. Joy Derwenskus has served as a Speaker and/or Consultant for EMD Serono, Genzyme, a Sanofi Company, Novartis, and Teva Pharmaceuticals USA. Susan Allen, Stephanie LaPointe, Melissa Nelson, Stacey Ness, and Libin Philip have no relevant commercial and/or financial relationships to disclose. Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature

ProCE, Inc. 848 W. Bartlett Road Suite 11E Bartlett, IL 60103 www.ProCE.com

MS-102: Navigating the MS Therapeutic Landscape September 2017 (update) Ocrelizumab Ocrevus 300mg intravenously on day 1 and 15, then 600mg every 6 months monoclonal antibody approved by FDA in 2017

ARR: annualized relapse rate; CDP: confirmed disability progression; CEL: contrast/Gd-enhacing lesion; WML: while matter lesion; % reported as relative risk reduction; Ocrevus [package insert]. South San Francisco, CA: Genentech Inc, 2017.

• Common Adverse Effects – Infusion reaction – Respiratory tract infection – Skin infection – Serious Adverse Effects – Infusion reaction – Malignancy (breast cancer)

• Contraindications – Active hepatitis B virus infection

• Infusion Reaction – Up to 40% of patients – May occur up to 24 hours

after infusion – pruritus, rash, urticaria, erythema, bronchospasm,

throat irritation, dyspnea, laryngeal edema, flushing, hypotension, HA, dizziness, nausea, tachycardia

– Premed with steroids + antihistamines +/- antipyretic – Monitor vitals during infusion and at least 24 hours

after • Follow standard breast cancer screening guidelines • Baseline Hepatitis B virus screening required

•Humanized monoclonal antibody•Binds CD20 on B lymphocytes to promote cytolysisMechanism

• Relapsing forms of MS• Primary Progressive MS

Indication

•↓ ARR by 46%•↓ CDP by 40%•↓ CELs by 94%; ↓WMLs by 77-83%

Efficacy vs IFN beta-1a SUBQ

(RRMS)

•↓ CDP by 24%Efficacy vs placebo

(PPMS)

High Efficacy

Mod/High Toxicity

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Thank you for joining us today. My name is Brandon

Markley and I am joined by my colleague, Aimee

Banks. We are both clinical pharmacists at

Vanderbilt University Medical Center in Nashville,

Tennessee where we work in the Department of

Specialty Pharmacy and our practice site is the

Vanderbilt Multiple Sclerosis Clinic. The title of

today’s presentation is “Navigating the MS

Therapeutic Landscape,” which is the second CE

activity in a four-part series.

I have no conflicts of interest or financial

relationships to disclose.

The learning objectives of this presentation are to

differentiate the platform disease-modifying

therapies and oral and injectable multiple sclerosis

therapies with regard to efficacy, safety and

tolerability and immunological activity; recognize

how the product is supplied and how to properly

administer, as well as store each disease-modifying

therapy; and finally, outline the latest evidence-

based therapeutic regimens for relapsing MS,

including staging, sequencing and combination

treatment across care settings.

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Learning Objectives

• Differentiate the “platform” Disease-Modifying Therapies (DMTs) and newer oral and injectable Multiple Sclerosis (MS) therapies with regard to efficacy, safety and tolerability, and immunological activity.

• Recognize how the product is supplied and how to properly administer as well as store each disease-modifying therapy.

• Outline the latest evidence-based therapeutic regimens for relapsing MS, including staging, sequencing, and combination treatment across care settings.

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Learning Objectives

• Differentiate the “platform” Disease-Modifying Therapies (DMTs) and newer oral and injectable Multiple Sclerosis (MS) therapies with regard to efficacy, safety and tolerability, and immunological activity.

• Recognize how the product is supplied and how to properly administer as well as store each disease-modifying therapy.

• Outline the latest evidence-based therapeutic regimens for relapsing MS, including staging, sequencing, and combination treatment across care settings.

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Aimee M. Banks, PharmD, BCPSBrandon M. Markley, PharmD, BCPS

Clinical PharmacistsVanderbilt University Medical Center

Multiple Sclerosis ClinicNashville, Tennessee

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Faculty

Brandon M. Markley, PharmD, BCPSClinical Pharmacists

Vanderbilt University Medical Center


It is the policy of ProCE, Inc., Wild Iris Medical Education, Inc., and NASP to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation.

Disclosure: Dr. Markley has no relevant commercial and/or financial


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Faculty

Brandon M. Markley, PharmD, BCPSClinical Pharmacists




Disclosure: Dr. Markley has no relevant commercial and/or financial


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We’ll go ahead and begin this activity with an

example of a patient case which we will revisit

throughout the presentation. TK is a 37-year-old

female who was recently diagnosed with

relapsing-remitting MS. Her neurologist would like

to go ahead and begin therapy with an interferon.

Some things you want to begin thinking about

include - what are the key counseling points that

you would like to discuss with this patient? What

are the recommended monitoring parameters

going forward with the medication?

DMTs, Disease-Modifying Therapies, can be

broken down into three specific categories. We

have our platform therapies, our oral therapies

and our monoclonal antibodies. Our platform

therapies in which some individuals may describe

are our “older tried and true” medications,

include interferons and glatiramer acetate.

The oral therapies include fingolimod, teriflunomide and dimethyl fumarate. Our monoclonal antibodies include two IV infusions, natalizumab and alemtuzumab and our most recently FDA-approved medication, daclizumab,

which is a subcutaneous injectable.

This chart here provides some general

information for all of the disease-modifying

therapies such as the trade name, the starting

dose, which is going to be applicable to the

interferons, as well as our oral medication,

dimethyl fumarate; the target dose or the

maintenance dose throughout therapy; the route

of administration…so is it a subQ injectable,

intramuscular injectable, an oral therapy, or an IV

infusion; the frequency that the dose is given, and

some specific notes regarding the medication. For

example, is it a limited distribution drug such as

PegIFN or dimethyl fumarate?

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TK is a 37 year old female, who was recently diagnosed with relapsing-remitting multiple sclerosis.

Her neurologist would like to initiate treatment with interferon therapy.

What are some key counseling points about interferons to discuss with her?

What are the recommended monitoring parameters for interferons?

44

TK is a 37 year old female, who was recently diagnosed with relapsing-remitting multiple sclerosis.

Her neurologist would like to initiate treatment with interferon therapy.


What are the recommended monitoring parameters for interferons?

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DMTs At-a-Glance*

“Platform” Therapies

Interferons

1993

Glatiramer acetate

1997

Oral Therapies

Fingolimod

2010

Teriflunomide

2012

Dimethyl fumarate

2013

Monoclonal Antibodies

Natalizumab

2004

Alemtuzumab

2014

Daclizumab

2016

* Listed by year of initial FDA approval for MS

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DMTs At-a-Glance*

“Platform” Therapies

Interferons

1993

Glatiramer acetate

1997

Oral Therapies

Fingolimod

2010

Teriflunomide

2012

Dimethyl fumarate

2013

Monoclonal Antibodies

Natalizumab

2004

Alemtuzumab

2014

Daclizumab

2016

* Listed by year of initial FDA approval for MS

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Drug name Trade name Starting dose Target dose Route Frequency Notes

IFN beta-1bBetaseron/

Extavia 0.0625mg 0.25mg SubQ Every other day 0.25mg/mL after reconstitution (0.3mg per vial)

IFN beta-1a IM Avonex 7.5mcg 30mcg IM Every 7 daystitration with syringes only (using AvoStart Grip)

IFN beta-1a SubQ Rebif8.8mcg 44mcg SubQ 3x per week 22mcg available

PegIFN-beta-1a Plegridy63mcg 125mcg SubQ Every 14 days LDD

Glatiramer 20mg

Copaxone/

Glatopa

n/a 20mg SubQ Once daily

Glatiramer 40mg Copaxonen/a 40mg SubQ 3x per week

Fingolimod Gilenya n/a 0.5mg Oral Once daily

Teriflunomide Aubagion/a 14mg Oral Once daily LDD; 7mg available

Dimethyl fumarate Tecfidera 120mg 240mg Oral Twice daily LDD

Natalizumab Tysabrin/a 300mg IV Every 28 days

Alemtuzumab Lemtrada n/a 12mg IV Every 12 monthsYear 1: 12mg x5daysYear 2: 12mg x3days

DaclizumabZinbryta n/a 150mg SubQ Every 28 days LDD

LDD: limited distribution drugBetaseron [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.; Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.; Avonex [package insert]. Cambridge, MA: Biogen Idec Inc; 2015.; Rebif [package insert]. Rockland, MA: EMD Serono, Inc.; 2015.; Plegridy [package insert]. Cambridge, MA: Biogen Idec Inc: 2015.; Copaxone [package insert].North Wales, PA: Teva Pharmaceuticals; 2014.; Glatopa [package insert]. Princeton, NJ: Sandoz Inc; 2015.; Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. ; Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; 2014.; Tecfidera [package insert]. Cambridge, MA: Biogen Inc; 2015.; Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc; 2012.; Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; 2014.; Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016.

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Drug name Trade name Starting dose Target dose Route Frequency Notes

IFN beta-1bBetaseron/

Extavia 0.0625mg 0.25mg SubQ Every other day 0.25mg/mL after reconstitution (0.3mg per vial)

IFN beta-1a IM Avonex 7.5mcg 30mcg IM Every 7 daystitration with syringes only (using AvoStart Grip)

IFN beta-1a SubQ Rebif8.8mcg 44mcg SubQ 3x per week 22mcg available

PegIFN-beta-1a Plegridy63mcg 125mcg SubQ Every 14 days LDD

Glatiramer 20mg

Copaxone/

Glatopa

n/a 20mg SubQ Once daily

Glatiramer 40mg Copaxonen/a 40mg SubQ 3x per week

Fingolimod Gilenya n/a 0.5mg Oral Once daily

Teriflunomide Aubagion/a 14mg Oral Once daily LDD; 7mg available

Dimethyl fumarate Tecfidera 120mg 240mg Oral Twice daily LDD

Natalizumab Tysabrin/a 300mg IV Every 28 days

Alemtuzumab Lemtrada n/a 12mg IV Every 12 monthsYear 1: 12mg x5daysYear 2: 12mg x3days

DaclizumabZinbryta n/a 150mg SubQ Every 28 days LDD

LDD: limited distribution drugBetaseron [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.; Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.; Avonex [package insert]. Cambridge, MA: Biogen Idec Inc; 2015.; Rebif [package insert]. Rockland, MA: EMD Serono, Inc.; 2015.; Plegridy [package insert]. Cambridge, MA: Biogen Idec Inc: 2015.; Copaxone [package insert].North Wales, PA: Teva Pharmaceuticals; 2014.; Glatopa [package insert]. Princeton, NJ: Sandoz Inc; 2015.; Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. ; Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; 2014.; Tecfidera [package insert]. Cambridge, MA: Biogen Inc; 2015.; Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc; 2012.; Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; 2014.; Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016.

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Before diving into the specific therapies, it’s

important to understand how we define their

efficacy. For example, we want to see a reduction

of clinical relapses, which is measured by the

annualized relapse rate, as well as a delay in

disability progression and finally, a reduction of

new MRI lesions, which are going to be

measured through MRI outcomes.

Starting off with our first class of medications,

interferons. Interferons work by reducing central

nervous system, or CNS, inflammation through

the inhibition of T-cell activation, proliferation

and migration. They have indications for both

relapsing forms of MS, as well as CIS, or Clinically

Isolated Syndrome.

It is important to note that only three interferon products have the indication for CIS and that’s IFN beta-1a IM, or Avonex and our two interferon beta-1b products, Betaseron and Extavia. We consider interferons to have

moderate efficacy when it comes to treating MS, and they show an annual relapse rate reduction by approximately 30-35%.

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Interferons (IFNs)

• Reduce Central Nervous System (CNS) inflammation by inhibiting T-cell activation, proliferation, and migration into CNS

Mechanism

• Relapsing forms of MS

• Clinically Isolated Syndrome (CIS) (IFN beta-1a IM, IFN beta-1b)

Indication

• ↓ Annual Relapse Rate (ARR) by 30-35%

• ↓ CDP by 30-40%

• ↓ CELs by 30-80%; ↓WMLs by 5-20%

Efficacy vs placebo

RRMS

Avonex [package insert]. Cambridge, MA: Biogen Idec Inc; 2015.; Betaseron [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.; Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.; Plegridy [package insert]. Cambridge, MA: Biogen Idec Inc: 2015.; Rebif [package insert]. Rockland, MA: EMD Serono, Inc.; 2015.; Neurologist. 2015; 19(4): 104-117. Neurology. 1993; 43(4): 662-667; Ann Neurol. 1996; 39(3): 285-294; Lancet. 1998; 352(9139): 1498-504; Lancet Neurol. 2014; 13(7): 657-665.

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Interferons (IFNs)

• Reduce Central Nervous System (CNS) inflammation by inhibiting T-cell activation, proliferation, and migration into CNS

Mechanism


• Clinically Isolated Syndrome (CIS) (IFN beta-1a IM, IFN beta-1b)

Indication

• ↓ Annual Relapse Rate (ARR) by 30-35%

• ↓ CDP by 30-40%

• ↓ CELs by 30-80%; ↓WMLs by 5-20%

Efficacy vs placebo

RRMS

Avonex [package insert]. Cambridge, MA: Biogen Idec Inc; 2015.; Betaseron [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015.; Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.; Plegridy [package insert]. Cambridge, MA: Biogen Idec Inc: 2015.; Rebif [package insert]. Rockland, MA: EMD Serono, Inc.; 2015.; Neurologist. 2015; 19(4): 104-117. Neurology. 1993; 43(4): 662-667; Ann Neurol. 1996; 39(3): 285-294; Lancet. 1998; 352(9139): 1498-504; Lancet Neurol. 2014; 13(7): 657-665.

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Defining EfficacyReduction of Clinical Relapses

• Measured as ARR (Annualized Relapse Rate)

Delay of disability progression

• Measured as CDP (Confirmed Disability Progression)

• By EDSS* score

Reduction of new lesions

• Measured as MRI outcomes

• CEL: Contrast/Gd-Enhancing Lesion on T1 MRI

• WML: new/enlarging White Matter Lesion on T2 MRI

• cBH: chronic Black Holes on T1 MRI

• BPF: Brain Parenchymal Fraction, aka brain atrophy

*EDSS- Expanded Disability Status ScalePawate S, Bagnato F. Newer agents in the treatment of multiple sclerosis. Neurologist. 2015 Apr;19(4): 104-1777

Defining EfficacyReduction of Clinical Relapses

• Measured as ARR (Annualized Relapse Rate)

Delay of disability progression

• Measured as CDP (Confirmed Disability Progression)

• By EDSS* score

Reduction of new lesions

• Measured as MRI outcomes

• CEL: Contrast/Gd-Enhancing Lesion on T1 MRI

• WML: new/enlarging White Matter Lesion on T2 MRI

• cBH: chronic Black Holes on T1 MRI

• BPF: Brain Parenchymal Fraction, aka brain atrophy

*EDSS- Expanded Disability Status ScalePawate S, Bagnato F. Newer agents in the treatment of multiple sclerosis. Neurologist. 2015 Apr;19(4): 104-17

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Interferons can cause both injection site

reactions and flu-like symptoms, which tend to

be one of the more commonly-reported side

effects when it comes to these medications.

Approximately 92% of patients at some point will

report experiencing injection site reactions-

which can manifest itself as pain, erythema or

swelling and bruising at the injection site.

Our subQ interferons tend to have more injection site reactions than our intramuscular formulation. However, it is important to note that the incidence does tend to decrease after

the first three months of therapy. Approximately 60% of patients reported experiencing flu-like symptoms in clinical trials. They tend to occur two-to-eight hours after the dose is given and tend to resolve within the first day. They do improve with continued dosing and the frequency does tend to be greatest with our intramuscular formulation, Avonex.

Interferons have also been shown to cause LFT

abnormalities. However, they typically tend to be

asymptomatic and are rarely severe. The

incidence does vary between trials and we tend

to see our greatest risk for LFT elevations within

the first year of therapy, thus it’s important to

monitor liver function tests at one, three and six

months and then periodically as the patient

proceeds forward with therapy.

All of our interferon products have been associated with both leukopenia and lymphopenia. However, the good news here is

that it’s often mild and rarely requires treatment discontinuation. Monitoring of the complete blood cell count, or CBC, with differential is important at one, three and six months and then periodically going forward. I would like to point out obtaining a CBC with differential is important as the differential component does include the lymphocyte counts, which is an important monitoring parameter throughout therapy.

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Interferons• Injection Site Reactions

• Flu-like symptoms – Incidence ~60% in clinical trials

– 2-8 hours post-dose; resolution after ~24 hours

– Improves with continued dosing

– Frequency greatest with IFN beta-1a IM

Brandes DW et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009 Jan;25(1):77-92.Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs 2005;19(3):239-52Subei AM, Ontaneda D. Risk Mitigation Strategies for Adverse Reactions Associated with the Disease-Modifying Drugs in Multiple Sclerosis. CNS Drugs 2015 Sep;29(9):759-71Lanzillo R et al. Vitamin K cream reduces reactions at the injection site in patients with relapsing-remitting multiple sclerosis treated with subcutaneous interferon beta - VIKING study. Mult Scler 2015 Aug;21(9):1215-6

92% of patients

Pain

Erythema

Swelling/bruising

SubQ > IMIncidence ↓

after ~3 months

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Interferons• Injection Site Reactions

• Flu-like symptoms – Incidence ~60% in clinical trials

– 2-8 hours post-dose; resolution after ~24 hours

– Improves with continued dosing

– Frequency greatest with IFN beta-1a IM

Brandes DW et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009 Jan;25(1):77-92.Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs 2005;19(3):239-52Subei AM, Ontaneda D. Risk Mitigation Strategies for Adverse Reactions Associated with the Disease-Modifying Drugs in Multiple Sclerosis. CNS Drugs 2015 Sep;29(9):759-71Lanzillo R et al. Vitamin K cream reduces reactions at the injection site in patients with relapsing-remitting multiple sclerosis treated with subcutaneous interferon beta - VIKING study. Mult Scler 2015 Aug;21(9):1215-6

92% of patients

Pain

Erythema

Swelling/bruising

SubQ > IMIncidence ↓

after ~3 months

1010

Interferons• LFT Abnormalities

– Rarely severe or symptomatic– Incidence 4-27% in clinical trials– Greatest risk during 1st year– Monitor Liver Function Tests (LFTs) at 1, 3, and 6 months, then

“periodically”

• Leukopenia/Lymphopenia– ↓ WBC and lymphocytes with all IFNs– Often mild and does NOT warrant discontinuation– Monitor Complete Blood Count (CBC) w/ differential at 1, 3, and

6 months, then “periodically”

Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs 2005;19(3):239-52Tremlett H, Oger J. Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis. J Neurol 2004 Nov;251(11):1297-303.Brandes DW et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009 Jan;25(1):77-92.

1010

Interferons• LFT Abnormalities

– Rarely severe or symptomatic– Incidence 4-27% in clinical trials– Greatest risk during 1st year– Monitor Liver Function Tests (LFTs) at 1, 3, and 6 months, then

“periodically”

• Leukopenia/Lymphopenia– ↓ WBC and lymphocytes with all IFNs– Often mild and does NOT warrant discontinuation– Monitor Complete Blood Count (CBC) w/ differential at 1, 3, and

6 months, then “periodically”

Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs 2005;19(3):239-52Tremlett H, Oger J. Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis. J Neurol 2004 Nov;251(11):1297-303.Brandes DW et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009 Jan;25(1):77-92.

8

All of our interferons have been associated with

the risk of depression. However, the incidence

does vary and clinical trials seem to have

produced mixed results. The concern here is not

so much interferons causing depression, but

more so that they may worsen a pre-existing

condition. Thus, patients do need to be screened

for depression before they begin therapy, as well

as adequate counseling should be provided

throughout.

Moving on to our next platform therapy,

glatiramer acetate. Glatiramer works a little bit

differently versus our interferons in that it

actually mimics myelin protein and blocks T-cell

mediated damage to the myelin. Just like our

interferons, it does have an indication for both

relapsing-remitting MS, as well as CIS. Annualized

relapse rates have decreased by 30-35% in trials

and it’s important to note that they actually did

not show any significant effect on disability

progression.

Just like interferons, injection site reactions are

quite common with the use of glatiramer. Pain,

erythema, swelling and pruritus can be

experienced at the injection site. A dose

comparison trial, looking at the 20mg and 40mg

formulations, did show that there was no

significant difference in the injection site

reaction incidence.

Glatiramer can also cause lipoatrophy, which is a localized loss of subcutaneous fat at the injection site. This can really occur with any subcutaneous therapy, however, it does seem to

be most prevalent with glatiramer 20mg. Unfortunately, this side effect is often permanent and disfiguring and is thought to be caused by a combination of an allergic reaction at the site and repeated mechanical injury.

1111

Interferons

• Depression

– Risk with all IFNs

– Incidence varies/clinical trials have produced mixed results

– Concern is IFNs may worsen pre-existing depression

– Patients should be screened for depression prior to therapy initiation, and adequate ongoing counseling should be provided

Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin. 2009 Jan;25(1):77-92

1111

Interferons

• Depression

– Risk with all IFNs

– Incidence varies/clinical trials have produced mixed results

– Concern is IFNs may worsen pre-existing depression

– Patients should be screened for depression prior to therapy initiation, and adequate ongoing counseling should be provided

Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin. 2009 Jan;25(1):77-92

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Glatiramer acetate (GA)

• Synthetic protein that mimics myelin basic protein (MBP) and blocks T-cell mediated damage to myelin

Mechanism

• Relapsing-remitting MS

• CISIndication

• ↓ ARR by 30-35%

• ↓ CDP not significant

• ↓ CELs by 35-45%; ↓WMLs up to 35%

Efficacy vs placebo

(RRMS)

Copaxone [package insert].North Wales, PA: Teva Pharmaceuticals; 2014.Glatopa [package insert]. Princeton, NJ: Sandoz Inc; 2015.Johnson KP et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 1995; 45(7): 1268-1276. Khan O et al. Three times weekly glatiramer acetate in relapsing–remitting multiple sclerosis. Ann Neurol. 2013; 73(6): 705-713.

1212

Glatiramer acetate (GA)

• Synthetic protein that mimics myelin basic protein (MBP) and blocks T-cell mediated damage to myelin

Mechanism

• Relapsing-remitting MS

• CISIndication

• ↓ ARR by 30-35%

• ↓ CDP not significant

• ↓ CELs by 35-45%; ↓WMLs up to 35%

Efficacy vs placebo

(RRMS)

Copaxone [package insert].North Wales, PA: Teva Pharmaceuticals; 2014.Glatopa [package insert]. Princeton, NJ: Sandoz Inc; 2015.Johnson KP et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 1995; 45(7): 1268-1276. Khan O et al. Three times weekly glatiramer acetate in relapsing–remitting multiple sclerosis. Ann Neurol. 2013; 73(6): 705-713.

1313

Glatiramer acetate• Injection Site Reactions

– Incidence up to 90%– Local pain, erythema, swelling, pruritus– Dose comparison trial: no significant difference in

incidence between 20mg vs 40mg

• Lipoatrophy– Localized loss of subcutaneous fat– Can occur with any SubQ DMT

• Most prevalent with glatiramer acetate 20mg

– Permanent and often disfiguring– Thought to be caused by “allergic” reaction and

mechanical injury

Comi G et al. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol. 2011 Jan;69(1):75-82.La Mantia L et al. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010 May 12;(5):CD004678.

1313

Glatiramer acetate• Injection Site Reactions

– Incidence up to 90%– Local pain, erythema, swelling, pruritus– Dose comparison trial: no significant difference in

incidence between 20mg vs 40mg

• Lipoatrophy– Localized loss of subcutaneous fat– Can occur with any SubQ DMT

• Most prevalent with glatiramer acetate 20mg

– Permanent and often disfiguring– Thought to be caused by “allergic” reaction and

mechanical injury

Comi G et al. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol. 2011 Jan;69(1):75-82.La Mantia L et al. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010 May 12;(5):CD004678.

9

Glatiramer can also cause an IPIR, or immediate

post-injection reaction. This is essentially a

systemic reaction that can occur immediately

following the dose. The patient may experience

some chest tightness and flushing. They might

feel their heart start to race. They may feel

short of breath and they may have a feeling of

anxiousness or anxiety come over them.

It’s important to let them know this is very self-limiting and transient, and should self-resolve on its own very quickly. In a dose comparison trial, there was a similar reported incidence

between the two different formulations, 20mg and the 40mg.

Moving on to our oral therapies, we’ll go ahead

and begin with fingolimod. Fingolimod works

by sequestering the lymphocytes into lymph

nodes, thus reducing their migration into the

CNS. It has an indication for relapsing forms of

MS and has been shown to decrease the

annualized relapse rate by over 50%. Also

notable with fingolimod is its decrease in brain

atrophy by up to 30%.

1414

Glatiramer acetate

• Immediate post-injection reaction (IPIR)

– Systemic reaction that occurs following injection

– Flushing, chest tightness, palpitations, dyspnea, anxiety

– Transient/self limiting with spontaneous recovery

– Dose comparison trial: similar reported incidence between 20mg versus 40mg

Comi G et al. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol 2011 Jan;69(1):75-82.La Mantia L et al. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev 2010 May 12;(5):CD004678

1414

Glatiramer acetate

• Immediate post-injection reaction (IPIR)

– Systemic reaction that occurs following injection

– Flushing, chest tightness, palpitations, dyspnea, anxiety

– Transient/self limiting with spontaneous recovery

– Dose comparison trial: similar reported incidence between 20mg versus 40mg

Comi G et al. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol 2011 Jan;69(1):75-82.La Mantia L et al. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev 2010 May 12;(5):CD004678

1515

Fingolimod

• Sphingosine 1-receptor modulator to sequester lymphocytes into lymph nodes and reduce migration into CNSMechanism

• Relapsing forms of MSIndication

• ↓ ARR by 54%

• ↓ CDP by 30%

• ↓ CELs by 82%; ↓WMLs by 74%; ↓ cBH by 66%; ↓ BPF by 30%

Efficacy vs placebo

(RRMS)

Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.Kappos L et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. N Engl J Med. 2010; 362: 387-401.

1515

Fingolimod

• Sphingosine 1-receptor modulator to sequester lymphocytes into lymph nodes and reduce migration into CNSMechanism


• ↓ ARR by 54%

• ↓ CDP by 30%

• ↓ CELs by 82%; ↓WMLs by 74%; ↓ cBH by 66%; ↓ BPF by 30%

Efficacy vs placebo

(RRMS)

Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.Kappos L et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. N Engl J Med. 2010; 362: 387-401.

10

Fingolimod has been shown to cause a transient

bradycardia effect. There is a reported incidence

of 4% in clinical trials and you’d expect to see an

approximate eight beats per minute decrease

following the dose. The onset is typically within

one hour and we should see a full recovery

within 8-10 hours after the dose is given.

Because of this, patients first need to undergo a first dose observation, or what we call an FDO. This is when fingolimod is administered under a controlled setting in which hourly blood pressure and heart rate is taken for a total of six

hours. QT prolongation can also be a potential side effect with the use of fingolimod. However, the FDA-approved dose, 0.5mg, did not show any clinically significant QT prolongation in trials. However, clinically significant change was seen with two non-FDA approved doses, 1.25mg and 2.5mg. With that being said, it’s still important to monitor an ECG before the FDO process has begun, as well as at the completion. Because of these two risks, bradycardia and QT prolongation, it’s important for healthcare professionals to obtain an accurate medication history before beginning this first dose observation. This list needs to be screened for potential drug interactions, specifically looking at medications that may reduce the heart rate or prolong the QT interval. Examples include our beta-blockers, our non-dihydro calcium channel blockers, or fluoroquinolone antibiotics. Another important note is that Class 1a and III anti-arrhythmics are contraindicated with the use of fingolimod. Thus, if patients are on either one of these therapies, we cannot start fingolimod. With other interacting medications, for example, our other QT prolonging medications such as fluoroquinolone antibiotics or beta blockers, it’s important to note that we don’t necessarily need to withhold the use of fingolimod in this situation. We can actually hold the offending medication for approximately five-to-seven half-lives before the first dose observation with the ability to restart these medications—these offending medications—approximately two weeks after the first dose observation. The risk for this drug-drug interaction does tend to subside after fingolimod has saturated certain receptors.

1616

Fingolimod• Bradycardia

– Incidence 4% in clinical trials– Transient HR ↓ by ~8 beats per minute

• Onset ~1 hour post-dose; recovery by 8-10 hours post-dose

– First Dose Observation (FDO) required• Under controlled setting → hourly BP/HR x 6 hours

• QTc Prolongation– 0.5mg dose did NOT reveal clinically relevant QTc prolongation,

however at-risk patients were excluded• Clinically significant change with 1.25mg and 2.5mg dose

– Monitor ECG prior to FDO and at completion

Gilenya [package insert]. East Hanover, NJ: Novartis Corp 2016.Concentra Operating Corporation. Novartis Gilenya FDO program clinical protocol and highlights from prescribing information (PI). Available at: www.concentra.com/-/media/files/fdo/novartis-program-clinical-protocol.pdf?la=en. www.concentra.com/-/media/files/fdo/QT-Prolongation-Drug-List.pdf Accessed September 29, 2016.

*Screen for other medications that reduce HR and/or prolong QTc interval*Class Ia and III anti-arrhythmics are contraindicated

Hold others 5-7 half-lives prior to FDO; may restart 10-14 days post-FDO

1616

Fingolimod• Bradycardia

– Incidence 4% in clinical trials– Transient HR ↓ by ~8 beats per minute

• Onset ~1 hour post-dose; recovery by 8-10 hours post-dose

– First Dose Observation (FDO) required• Under controlled setting → hourly BP/HR x 6 hours

• QTc Prolongation– 0.5mg dose did NOT reveal clinically relevant QTc prolongation,

however at-risk patients were excluded• Clinically significant change with 1.25mg and 2.5mg dose

– Monitor ECG prior to FDO and at completion

Gilenya [package insert]. East Hanover, NJ: Novartis Corp 2016.Concentra Operating Corporation. Novartis Gilenya FDO program clinical protocol and highlights from prescribing information (PI). Available at: www.concentra.com/-/media/files/fdo/novartis-program-clinical-protocol.pdf?la=en. www.concentra.com/-/media/files/fdo/QT-Prolongation-Drug-List.pdf Accessed September 29, 2016.

*Screen for other medications that reduce HR and/or prolong QTc interval*Class Ia and III anti-arrhythmics are contraindicated

Hold others 5-7 half-lives prior to FDO; may restart 10-14 days post-FDO

11

Headache can also be caused by fingolimod and

tends to be most prominent and severe within

the first two weeks and should subside with

continued therapy. Macular edema is also a

potential side effect and tends to occur within

the first few months of therapy. Patients may

actually be asymptomatic or they may experience

blurred vision or decreased visual acuity. Because

of this, an ophthalmic exam does need to be

completed before we begin treatment, three-to-

four months after we start fingolimod and then,

as needed.

Fingolimod has also been known to cause LFT

abnormalities. Typically we see this within the

first year of therapy and even further more

specific, within the first six-to-nine months. For

patients that have pre-existing liver disease, this

does warrant caution because the half-life with

the drug is actually increased, leading to

increased drug exposure. Liver function tests do

need to be monitored prior to starting therapy, as

well as as-needed if there are any signs or

symptoms of hepatic dysfunction.

Herpes infections were shown to be present with the use of fingolimod in trials. Thus, patients need to first obtain a varicella zoster virus antibody prior to beginning therapy. If patients are negative, they need to be vaccinated with the VZV vaccine. Following the vaccination course, we need to postpone or withhold fingolimod for at least one month to allow immunity to develop.

1717

Fingolimod• Headache

– 25% incidence in clinical trials– Most prominent/severe in first ~2 weeks; ↓ with

continued therapy

• Macular Edema– Predominantly in first 3-4 months of therapy– Blurry vision/decreased visual acuity

• May be asymptomatic

– Obtain ophthalmic exam prior to treatment, 3-4 months after initiation, and prn for visual disturbances

Gilenya [package insert]. East Hanover, NJ: Novartis Corp, 2016.

1717

Fingolimod• Headache

– 25% incidence in clinical trials– Most prominent/severe in first ~2 weeks; ↓ with

continued therapy

• Macular Edema– Predominantly in first 3-4 months of therapy– Blurry vision/decreased visual acuity

• May be asymptomatic

– Obtain ophthalmic exam prior to treatment, 3-4 months after initiation, and prn for visual disturbances


1818

Fingolimod• LFT Abnormalities

– 14% experienced LFT elevations > 3x ULN• Majority within 6-9 months

– Pre-existing liver disease warrants caution– Monitor LFTs prior to initiation and prn if s/s of hepatic

dysfunction develop

• Herpes Infection– 9% incidence in trials – Varicella Zoster Virus (VZV) antibody- negative patients

should receive VZV vaccine• Postpone fingolimod x 1 month after vaccination

Gilenya [package insert]. East Hanover, NJ: Novartis Corp 2016.Arvin AM et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol 2015 Jan;72(1):31-9.

1818

Fingolimod• LFT Abnormalities

– 14% experienced LFT elevations > 3x ULN• Majority within 6-9 months

– Pre-existing liver disease warrants caution– Monitor LFTs prior to initiation and prn if s/s of hepatic

dysfunction develop

• Herpes Infection– 9% incidence in trials – Varicella Zoster Virus (VZV) antibody- negative patients

should receive VZV vaccine• Postpone fingolimod x 1 month after vaccination

Gilenya [package insert]. East Hanover, NJ: Novartis Corp 2016.Arvin AM et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol 2015 Jan;72(1):31-9.

12

Fingolimod can also cause a dose-dependent

decrease in the peripheral lymphocytes. We can

expect to see a decrease by approximately 20-

30% from baseline values. These may actually

persist for up to two months following the

discontinuation of therapy. Thus a CBC with

differential needs to be checked before we begin

therapy.

Fingolimod has also been associated with PML, or Progressive Multifocal Leukoencephalopathy. There have been 17 reported cases of PML in patients on fingolimod that had prior

natalizumab treatment and three reports in patients on fingolimod that did not have any prior natalizumab treatment.

Our next oral, teriflunomide, works a little bit

differently in that it’s a pyrimidine synthesis

inhibitor that works by decreasing the

proliferation of activated lymphocytes into the

CNS. It’s important to note that this is actually an

active metabolite of leflunomide, which you may

recall is an older medication used to treat

rheumatoid arthritis. Teriflunomide is indicated

for relapsing forms of MS and is shown to

decrease annualized relapse rate by

approximately 30%.

Gastrointestinal events can be somewhat

common with the use of teriflunomide and the

incidence is actually very similar between the

two different dosage formulations, the 7mg and

the 14mg. They tend to be more severe when

we first begin therapy and should resolve within

the first few weeks.

Alopecia has also been associated with teriflunomide, but it’s important to note this is not like chemotherapy-induced hair loss. It’s more of a slight, transient, diffuse hair thinning. Most patients report it as mild to moderate and

there have actually been no reports of complete hair loss. We tend to see the development of

1919

Fingolimod

• Leukopenia/Lymphopenia– Dose-dependent ↓ in peripheral lymphocytes

• Measured as absolute lymphocyte count (ALC)• ↓ ALC by 20-30% from baseline values

– Low WBC/ALC up to 2 months following discontinuation – Monitor CBC w/ differential prior to initiation

• PML (Progressive Multifocal Leukoencephalopathy)– Prior natalizumab treatment → 17 reports– No prior natalizumab treatment → 3 reports


1919

Fingolimod

• Leukopenia/Lymphopenia– Dose-dependent ↓ in peripheral lymphocytes

• Measured as absolute lymphocyte count (ALC)• ↓ ALC by 20-30% from baseline values

– Low WBC/ALC up to 2 months following discontinuation – Monitor CBC w/ differential prior to initiation

• PML (Progressive Multifocal Leukoencephalopathy)– Prior natalizumab treatment → 17 reports– No prior natalizumab treatment → 3 reports


2020

Teriflunomide

• Pyrimidine synthesis inhibitor to reduce proliferation of activated lymphocytes in CNS

• Active metabolite of leflunomideMechanism


• ↓ ARR by 32%

• ↓ CDP by 30%

• ↓ CELs by 80%; ↓WMLs by 77%; ↓ cBHs by 31%

Efficacy vs placebo

(RRMS)

Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; 2014. O’Connor P et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011; 365(14): 1293-1303.

2020

Teriflunomide

• Pyrimidine synthesis inhibitor to reduce proliferation of activated lymphocytes in CNS

• Active metabolite of leflunomideMechanism


• ↓ ARR by 32%

• ↓ CDP by 30%

• ↓ CELs by 80%; ↓WMLs by 77%; ↓ cBHs by 31%

Efficacy vs placebo

(RRMS)

Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; 2014. O’Connor P et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011; 365(14): 1293-1303.

2121

Teriflunomide• Gastrointestinal events

– Diarrhea and/or nausea/vomiting– 8-14% incidence in clinical trials (7mg ≈ 14mg)– Most pronounced after initiation, often self-resolves in ~2 weeks

• Alopecia– Up to 14% incidence in clinical trials (7mg ≈ 14mg)– Hair thinning/loss

• Transient, diffuse, and generalized over scalp• Mostly mild to moderate• No reports of complete hair loss

– Median time to onset ~ 3 months – Average duration < 6 months – > 80% of cases spontaneously improved with continued therapy

Aubagio [package insert]. Cambridge, MA: Genzyme Corp, 2016.

2121

Teriflunomide• Gastrointestinal events

– Diarrhea and/or nausea/vomiting– 8-14% incidence in clinical trials (7mg ≈ 14mg)– Most pronounced after initiation, often self-resolves in ~2 weeks

• Alopecia– Up to 14% incidence in clinical trials (7mg ≈ 14mg)– Hair thinning/loss

• Transient, diffuse, and generalized over scalp• Mostly mild to moderate• No reports of complete hair loss

– Median time to onset ~ 3 months – Average duration < 6 months – > 80% of cases spontaneously improved with continued therapy


13

alopecia within the first three months and the average duration is less than six months, and more than eight out of ten patients will have spontaneous improvement with continued therapy. So, in many instances, there is no need to stop therapy.

Teriflunomide does have a black box warning

when it comes to LFT abnormalities. This is

because severe and fatal liver failure has

occurred with the use of leflunomide. Thus,

similar risk is expected with teriflunomide.

Patients have a higher risk of having LFT

elevations if they have pre-existing liver

dysfunction. We tend to see these elevations

within the first year of starting therapy, thus we

want to check liver function tests before we

begin and then, monthly for the first six

months.

Both leukopenia and lymphopenia have also been associated with the use of teriflunomide. We tend to see a decrease in the white blood cell count within the first six weeks of therapy and while we don’t see any further decreases after that first six weeks, they do tend to remain low and we tend to not see a recovery. It’s important to check a CBC before we begin therapy with teriflunomide.

This medication is teratogenic, which is also a

black box warning. Animal studies have

indicated there is an increased risk of

teratogenic effects or fetal death with the use

of teriflunomide. It’s pregnancy Category X- for

all three trimesters.

For pregnant women, or women of childbearing potential who are not using reliable contraception, it’s important to note this therapy is contraindicated. A negative pregnancy test is recommended before we begin therapy with teriflunomide. Also,

teriflunomide is detected in human semen, thus men should also be counseled on using appropriate and reliable contraception.

2222

Teriflunomide• LFT Abnormalities (Black Box Warning)

– Severe/fatal liver failure has occurred with leflunomide• Similar risk expected with teriflunomide

– 13-15% incidence (7mg ≈ 14mg)– ↑ risk with pre-existing liver dysfunction – Elevations often during 1st yr of treatment– Monitor LFTs prior to initiation, then monthly x 6 mo

• Leukopenia/Lymphopenia– WBC ↓by 15% from baseline values (7mg ≈ 14mg)– ↓ Lymphocytes <800/mm3

• 10% of patients on 7mg dose• 12% of patients on 14mg dose

– ↓WBC often in first 6 weeks of therapy• Remain low (but stable) throughout therapy

– Monitor CBC prior to therapy initiation


2222

Teriflunomide• LFT Abnormalities (Black Box Warning)

– Severe/fatal liver failure has occurred with leflunomide• Similar risk expected with teriflunomide

– 13-15% incidence (7mg ≈ 14mg)– ↑ risk with pre-existing liver dysfunction – Elevations often during 1st yr of treatment– Monitor LFTs prior to initiation, then monthly x 6 mo

• Leukopenia/Lymphopenia– WBC ↓by 15% from baseline values (7mg ≈ 14mg)– ↓ Lymphocytes <800/mm3

• 10% of patients on 7mg dose• 12% of patients on 14mg dose

– ↓WBC often in first 6 weeks of therapy• Remain low (but stable) throughout therapy

– Monitor CBC prior to therapy initiation


2323

Teriflunomide

• Teratogenic (Black Box Warning)– Animal studies indicate ↑ risk of teratogenic effects or

fetal death– Pregnancy Category X (all trimesters)– Contraindicated in pregnant women OR women of

childbearing potential who are NOT using reliable contraception

• Negative pregnancy test recommended prior to initiation

– Teriflunomide is detected in human semen• Animal studies evaluating the risk of male-mediated fetal

toxicity have NOT been conducted• Men should use reliable contraception


2323

Teriflunomide

• Teratogenic (Black Box Warning)– Animal studies indicate ↑ risk of teratogenic effects or

fetal death– Pregnancy Category X (all trimesters)– Contraindicated in pregnant women OR women of

childbearing potential who are NOT using reliable contraception

• Negative pregnancy test recommended prior to initiation

– Teriflunomide is detected in human semen• Animal studies evaluating the risk of male-mediated fetal

toxicity have NOT been conducted• Men should use reliable contraception


14

Our last oral, dimethyl fumarate, works through

the Nrf2 pathway and produces both anti-

inflammatory and cytoprotective effects. Similar

to our other medications, it’s indicated for

relapsing forms of MS only. With dimethyl

fumarate, we should expect a decrease in

annualized relapse rate by approximately 53%.

The two most common reported side effects with

the use of dimethyl fumarate are flushing and

gastrointestinal events. Flushing typically occurs

about 30 minutes to several hours after the dose

is given. Most patients will describe it as mild to

moderate in severity and it’s important to note

that the incidence is highest within the first month

of treatment and we should see a sharp decrease

after that first month.

Gastrointestinal events, typically upper abdominal pain, nausea, vomiting, and diarrhea are also quite

common with the use of this therapy. In fact, a post-marketing study called MANAGE, demonstrated that 88% of patients reported a GI event, and 61% of those patients actually required therapy to help manage these symptoms. Just like with flushing, the highest incidence is going to be within the first few months of therapy and we should see a sharp decrease going forward.

Dimethyl fumarate has also been associated, like

our other therapies, with leukopenia and

lymphopenia. Lymphocytes can decrease by up

to 30%- typically we see this within the first year

and then, they do tend to remain stable

throughout therapy. Approximately 6% of

patients have experienced lymphocytes less than

500, or severe lymphopenia, and it’s important

to note that our elderly patients are going to be

at higher risk for developing either moderate or

severe lymphopenia.

2525

Dimethyl Fumarate• Flushing

– Incidence ~40% in trials– 30 minutes to several hours post-dose– Typically mild-moderate in severity– Highest in 1st month and ↓ thereafter

• Gastrointestinal Events– Upper abdominal pain, nausea/vomiting, diarrhea– Incidence varies by symptom: 5-18%– Post marketing study: MANAGE

• 88% of patients reported a GI event → 61% required therapy for symptomatic management

– Highest in 1st month and ↓ thereafter

Tecfidera [package insert]. Cambridge, MA: Biogen Inc, 2016.Fox EJ et a. Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE). Int J MS Care 2016 Jan-Feb;18(1):9-18.

2525

Dimethyl Fumarate• Flushing

– Incidence ~40% in trials– 30 minutes to several hours post-dose– Typically mild-moderate in severity– Highest in 1st month and ↓ thereafter

• Gastrointestinal Events– Upper abdominal pain, nausea/vomiting, diarrhea– Incidence varies by symptom: 5-18%– Post marketing study: MANAGE

• 88% of patients reported a GI event → 61% required therapy for symptomatic management

– Highest in 1st month and ↓ thereafter

Tecfidera [package insert]. Cambridge, MA: Biogen Inc, 2016.Fox EJ et a. Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE). Int J MS Care 2016 Jan-Feb;18(1):9-18.

2626

Dimethyl Fumarate• Leukopenia/Lymphopenia

– WBC ↓ by 11%– Lymphocytes ↓ by 30%

• Typically within first year, then remain stable

– 6% of patients experienced lymphocytes <500/mm3– ↑ age leads to ↑ risk for moderate-severe lymphopenia

• PML– 4 case reports

• 3 reports → severe lymphopenia (<500/mm3)• 1 case report → moderate lymphopenia (>500/mm3)• All occurred in setting of prolonged lymphopenia (> 6 months)

– Routine lab work• CBC w/ differential at baseline, 6 mo, then q 6-12 mo and prn

Tecfidera [package insert]. Cambridge, MA: Biogen Inc, 2016.Fox R, et al. Lymphocyte count reductions in relapsing-remitting multiple sclerosis (RRMS) patients treated with delayed release dimethyl fumarate: an Integrated analysis of the placebo-controlled studies. Neuro 2014;83(10) Suppl P3-179.

2626

Dimethyl Fumarate• Leukopenia/Lymphopenia

– WBC ↓ by 11%– Lymphocytes ↓ by 30%

• Typically within first year, then remain stable

– 6% of patients experienced lymphocytes <500/mm3– ↑ age leads to ↑ risk for moderate-severe lymphopenia

• PML– 4 case reports

• 3 reports → severe lymphopenia (<500/mm3)• 1 case report → moderate lymphopenia (>500/mm3)• All occurred in setting of prolonged lymphopenia (> 6 months)

– Routine lab work• CBC w/ differential at baseline, 6 mo, then q 6-12 mo and prn

Tecfidera [package insert]. Cambridge, MA: Biogen Inc, 2016.Fox R, et al. Lymphocyte count reductions in relapsing-remitting multiple sclerosis (RRMS) patients treated with delayed release dimethyl fumarate: an Integrated analysis of the placebo-controlled studies. Neuro 2014;83(10) Suppl P3-179.

2424

Dimethyl Fumarate (DMF)

• Activates Nrf2 pathway to produce anti-inflammatory and cytoprotective effectsMechanism


• ↓ ARR by 53%

• ↓ CDP by 40%

• ↓ CELs by 90%; ↓WMLs by 85%

Efficacy vs placebo

(RRMS)

Tecfidera [package insert]. Cambridge, MA: Biogen Inc; 2015.Gold R et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367(12): 1098-1107.

2424

Dimethyl Fumarate (DMF)

• Activates Nrf2 pathway to produce anti-inflammatory and cytoprotective effectsMechanism


• ↓ ARR by 53%

• ↓ CDP by 40%

• ↓ CELs by 90%; ↓WMLs by 85%

Efficacy vs placebo

(RRMS)

Tecfidera [package insert]. Cambridge, MA: Biogen Inc; 2015.Gold R et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367(12): 1098-1107.

15

There have been four PML case reports associated with the use of this drug. Three of those reports occurred under the setting of severe lymphopenia, so less than 500, and the last case report occurred when the patient experienced moderate lymphopenia. However, it is important to note that all did occur in the setting of prolonged lymphopenia where they experienced low values for over six months. Because of these case reports, it’s important to note that a CBC with differential should be obtained prior to beginning therapy, at six months, and then, every six-to-12 months going forward.

Moving on to our monoclonal antibodies, first is

natalizumab, which works by blocking T-cell

migration into the CNS. It has an indication for

relapsing forms of MS and we consider

natalizumab to be highly efficacious. As you can

see, it decreases our annualized relapse rates by

68%, contrast-enhancing lesions by over 90%

and white-matter lesions by over 80%.

Natalizumab therapy has been associated with

headache, fatigue, arthralgia, as well as rash.

The incidence does tend to be higher with

these side effects in patients that are being

treated with MS versus Crohn disease, which is

another indication for this therapy. Headaches

do tend to subside with continued dosing,

along with fatigue.

Arthralgia does seem to be twice as common in MS patients versus Crohn’s patients and again, typically should improve over time, and typically does not require any kind of

pharmacologic intervention.

2828

Natalizumab• Headache

– 38% incidence in MS trials• Similar amongst Crohn’s trials

– Tends to ↓ with continued dosing

• Fatigue– 27% incidence in MS trials

• vs 10% in Crohn disease trials

– Tends to improve over time

• Arthralgia– ~Twice as common in MS vs Crohn’s patients– Typically improves over time; rarely requires intervention

• Rash– ~Twice as common in MS vs Crohn’s patients

Tysabri [Package Insert]. Cambridge, MA: Biogen Inc., 2016

2828

Natalizumab• Headache

– 38% incidence in MS trials• Similar amongst Crohn’s trials

– Tends to ↓ with continued dosing

• Fatigue– 27% incidence in MS trials

• vs 10% in Crohn disease trials

– Tends to improve over time

• Arthralgia– ~Twice as common in MS vs Crohn’s patients– Typically improves over time; rarely requires intervention

• Rash– ~Twice as common in MS vs Crohn’s patients

Tysabri [Package Insert]. Cambridge, MA: Biogen Inc., 2016

2727

Natalizumab

• Humanized monoclonal antibody

• Binds α4 integrin to block T cell migration into CNS

Mechanism


• ↓ ARR by 68%

• ↓ CDP by 42%

• ↓ CELs by 92%; ↓WMLs by 83%; ↓ cBHs 76%

Efficacy vs placebo

(RRMS)

Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc, 2012.Polman CH et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354(9): 899-910.

2727

Natalizumab

• Humanized monoclonal antibody

• Binds α4 integrin to block T cell migration into CNS

Mechanism


• ↓ ARR by 68%

• ↓ CDP by 42%

• ↓ CELs by 92%; ↓WMLs by 83%; ↓ cBHs 76%

Efficacy vs placebo

(RRMS)

Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc, 2012.Polman CH et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354(9): 899-910.

16

Natalizumab can also cause an infusion

reaction which typically shows itself as

dizziness, fever, flushing, hypotension, and

dyspnea. It tends to occur within the first two

hours of starting the infusion and is often times

associated with the development of antibodies

to this drug. Thus, we want to go ahead and

test for antibodies if this is suspected. If the

antibody test is initially positive, we want to

repeat this after three months to actually

confirm the initial test was not a false positive.

Natalizumab has also been associated with hepatotoxicity, or LFT elevations. This can occur as early as six days after the first dose or it can occur after several doses. If the patient develops signs and symptoms of liver injury, we need to go ahead and stop therapy.

Natalizumab is also associated with PML, which

is a black box warning with this particular

medication. Three specific risk factors have

been identified that increase the risk for PML in

patients that are treated with natalizumab. This

is- increased treatment duration, particularly

over the first two year mark; the presence of

anti-JCV antibodies, and the use of prior

immunosuppressant therapy.

2929

Natalizumab• Infusion Reaction

– Dizziness, fever, flushing, hypotension, dyspnea

– Usually occurs within 2 hours of starting infusion

– Typically associated with antibodies to natalizumab• Antibody testing should be performed if suspicion

• If initially +, repeat after 3 months to confirm

• ↑ risk upon re-challenge (after discontinuation)

• Hepatotoxicity– LFT elevations: 5% incidence

– As early as 6 days after 1st dose, or after several doses

– S/S of liver injury warrant therapy discontinuation

– May reoccur with therapy re-challengeTysabri [Package Insert]. Cambridge, MA: Biogen Inc, 2016.

2929

Natalizumab• Infusion Reaction

– Dizziness, fever, flushing, hypotension, dyspnea

– Usually occurs within 2 hours of starting infusion

– Typically associated with antibodies to natalizumab• Antibody testing should be performed if suspicion

• If initially +, repeat after 3 months to confirm

• ↑ risk upon re-challenge (after discontinuation)

• Hepatotoxicity– LFT elevations: 5% incidence

– As early as 6 days after 1st dose, or after several doses

– S/S of liver injury warrant therapy discontinuation

– May reoccur with therapy re-challengeTysabri [Package Insert]. Cambridge, MA: Biogen Inc, 2016.

3030

Natalizumab• PML (Black Box Warning)

– 3 Risk factors:

↑ Treatment Duration (esp > 2 yrs)

Presence of anti-JCV antibodies

Prior immunosuppressant therapy

JCV: John Cunningham VirusTysabri [Package Insert]. Cambridge, MA: Biogen Inc, 2016.

3030

Natalizumab• PML (Black Box Warning)

– 3 Risk factors:

↑ Treatment Duration (esp > 2 yrs)

Presence of anti-JCV antibodies

Prior immunosuppressant therapy

JCV: John Cunningham VirusTysabri [Package Insert]. Cambridge, MA: Biogen Inc, 2016.

17

This table here highlights the estimated

incidence of natalizumab-induced PML

according to the three risk factors that we just

mentioned. For example, if the patient is anti-

JCV antibody negative, then they have a less

than 1/1000 chance of developing PML. As you

can see with this table, the risk of PML

increases as the duration of therapy increases

as well.

For example, if a patient has been on Tysabri between the 49-72 month timeframe and have not had any prior immunosuppressant therapy,

the risk is 6/1000. That same patient, if they were on prior immunosuppressant therapy, has a risk of 13/1000.

This next table here dissects the risk of PML a

little bit closer and that rather than just

reporting whether the patient is JCV positive or

negative, we actually have a numerical value

that is assigned to the JCV index. As you may

have predicted, the higher this numerical value,

the higher the risk for PML development.

For example, a patient who has been on natalizumab for five years, so they are going to fall under the far right column in regards to treatment duration, have an 8.5/1000 risk if their index is greater than 1.5 versus only a

1.3/1000 risk if their index is less than 1.5. You can see the assignment of a numerical value rather than just having a positive or negative result further aids in our risk stratification.

3131

Natalizumab

Tysabri [package insert]. Cambridge, MA: Biogen Inc, 2016.

PML Risk stratification

3131

Natalizumab

Tysabri [package insert]. Cambridge, MA: Biogen Inc, 2016.

PML Risk stratification

3232

Natalizumab

Plavina T et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2014; 76(6):802-12.

PML Risk stratification by index threshold

3232

Natalizumab

Plavina T et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2014; 76(6):802-12.

PML Risk stratification by index threshold

18

Because of the high risk of PML, natalizumab

does have a REMS program called the Tysabri

TOUCH Program in which access is restricted.

It’s important to monitor both MRI and anti-JCV

antibodies before you begin therapy, as well as

periodically throughout treatment. We need to

monitor for signs and symptoms suggestive of

PML for at least six months following

discontinuation of therapy.

Our next monoclonal antibody, also an IV infusion, is alemtuzumab. This particular medication works against both CD4 and CD8 T-cells, as well as B cells. It has an indication for relapsing forms of MS and can decrease annualized relapse rates by approximately 50%, as well as decrease disability progression by up to 40%.

Because of the risk for prolonged and severe

lymphopenia, infections can occur with the use

of alemtuzumab, particularly urinary tract

infections, upper respiratory tract infections,

herpetic infections, as well as influenza.

3434

Alemtuzumab

• Monoclonal antibody against CD52 on CD4 and CD8 T cells, B cells, eosinophils, macrophages, monocytesMechanism


• ↓ ARR by 50-55%

• ↓ CDP by up to 42%

• ↓ CELs up to 63%; ↓WMLs up to 32%; ↓ BPF by 24-41%

Efficacy vs

IFN beta-1a SubQ

(RRMS)

Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; 2014.Cohen JA et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012; 380(9856): 1819-1828.

3434

Alemtuzumab

• Monoclonal antibody against CD52 on CD4 and CD8 T cells, B cells, eosinophils, macrophages, monocytesMechanism


• ↓ ARR by 50-55%

• ↓ CDP by up to 42%

• ↓ CELs up to 63%; ↓WMLs up to 32%; ↓ BPF by 24-41%

Efficacy vs

IFN beta-1a SubQ

(RRMS)

Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; 2014.Cohen JA et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012; 380(9856): 1819-1828.

3535

Alemtuzumab• Infection

– Quite common due to severe and prolonged lymphopenia

Urinary Tract Infection

Upper Respiratory Tract Infection

Herpetic Infections

Influenza

Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.

3535

Alemtuzumab• Infection

– Quite common due to severe and prolonged lymphopenia

Urinary Tract Infection

Upper Respiratory Tract Infection

Herpetic Infections

Influenza


19

Alemtuzumab does have a black box warning

when it comes to infusion reactions. These have

been shown to be serious and life-threatening

and typically occur more than 24 hours after the

dose is given. Patients may experience

anaphylaxis, angioedema, hypotension,

bronchospasm, flushing, or chills. Pre-medicating

with corticosteroids can often help prevent the

onset of infusion reactions.

Alemtuzumab also has a black box warning for

both autoimmune disorders, as well as for

malignancy. Serious and fatal autoimmune

conditions such as thyroid disorders or immune

thrombocytopenia have occurred with the use of

alemtuzumab. Lab monitoring is especially

important - we need to check a CBC with

differential, serum creatinine and a urinalysis

monthly until 48 months after the last dose is

given. It’s also important to monitor thyroid

function as well, given the risk of thyroid

disorders.

As I just mentioned, malignancy is also a black box warning associated with alemtuzumab. Thus, this drug needs to be avoided in patients that have an active malignancy. It’s also recommended that both baseline and yearly skin exams be performed.

3737

Alemtuzumab• Autoimmune Disorders (Black Box Warning)

– Serious, fatal autoimmune conditions • Immune thrombocytopenia• Thyroid disorders

– Monitor CBC w/ differential, serum creatinine, and urinalysis monthly until 48 months after last dose

– Monitor thyroid function every 3 months until 48 months after last dose

• Malignancy (Black Box Warning)– May cause an increased risk of

• Thyroid cancer • Melanoma• Lymphoproliferative disorders

– AVOID in patients with an active malignancy– Perform baseline and yearly skin exams

Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.3737

Alemtuzumab• Autoimmune Disorders (Black Box Warning)

– Serious, fatal autoimmune conditions • Immune thrombocytopenia• Thyroid disorders

– Monitor CBC w/ differential, serum creatinine, and urinalysis monthly until 48 months after last dose

– Monitor thyroid function every 3 months until 48 months after last dose

• Malignancy (Black Box Warning)– May cause an increased risk of

• Thyroid cancer • Melanoma• Lymphoproliferative disorders

– AVOID in patients with an active malignancy– Perform baseline and yearly skin exams


3636

Alemtuzumab• Infusion Reactions (Black Box Warning)

– Serious, life-threatening reactions may occur

– Reported Incidence: 92%

– May occur > 24 hours post-dose

– Premed with corticosteroids

Anaphylaxis Angioedema Bronchospasm

Hypotension Chills Flushing


3636

Alemtuzumab• Infusion Reactions (Black Box Warning)

– Serious, life-threatening reactions may occur

– Reported Incidence: 92%

– May occur > 24 hours post-dose

– Premed with corticosteroids

Anaphylaxis Angioedema Bronchospasm

Hypotension Chills Flushing


20

Just like with natalizumab, alemtuzumab also

comes with a REMS program, called the

Lemtrada REMS program. This is because of the

black box warning risk that we just discussed:

infusion reactions, autoimmunity and

malignancies. This program does mandate

extensive labs prior to each infusion, monthly

during therapy and once again, for 48 months

after the last dose is given.

Moving on to our last monoclonal antibody and

our newest FDA-approved medication for MS

treatment, daclizumab. Daclizumab inhibits

interleukin-2 signaling and T-cell activation. It

does have an indication for relapsing forms of

MS, but it is important to point out here that

this therapy should be reserved for patients that

have an inadequate response to two or more

therapies. It has been shown to decrease

annualized relapse rates by approximately 45%

and just like glatiramer, it did not have any

clinically-significant effect on disability

progression.

Cutaneous adverse events have been reported

up to 37% in clinical trials and may actually take

up to three months to resolve. The use of this

medication may exacerbate any prior skin

conditions. Thus, the use of topical or systemic

corticosteroids may be required.

3939

Daclizumab• Humanized monoclonal antibody

• Binds CD25 to inhibit IL-2 signaling and T cell activation

Mechanism


• Should be reserved for patients with inadequate response to 2+ DMTs

Indication

• ↓ ARR by 45%

• ↓CDP not significant

• ↓WMLs by 54%

Efficacy vs

IFN beta-1a IM

(RRMS)

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016.Kappos L et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Eng J Med. 2015; 373(15): 1418-1428.

3939

Daclizumab• Humanized monoclonal antibody

• Binds CD25 to inhibit IL-2 signaling and T cell activation

Mechanism


• Should be reserved for patients with inadequate response to 2+ DMTs

Indication

• ↓ ARR by 45%

• ↓CDP not significant

• ↓WMLs by 54%

Efficacy vs

IFN beta-1a IM

(RRMS)

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016.Kappos L et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Eng J Med. 2015; 373(15): 1418-1428.

3838

Alemtuzumab

• REMS Program

– Access restricted through Lemtrada REMS Program

– Due to risk of infusion reactions, autoimmunity, and malignancies

– Mandates extensive labs prior to each infusion, monthly during therapy, and x 48 months after last dose


3838

Alemtuzumab

• REMS Program

– Access restricted through Lemtrada REMS Program

– Due to risk of infusion reactions, autoimmunity, and malignancies

– Mandates extensive labs prior to each infusion, monthly during therapy, and x 48 months after last dose


4040

Daclizumab

• Cutaneous Adverse Events

– Incidence upwards of 37% in clinical trials

– Mean time for rash resolution → 3 months

– Drug use may exacerbate prior eczema condition

– May require topical or systemic corticosteroids

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016.

4040

Daclizumab

• Cutaneous Adverse Events

– Incidence upwards of 37% in clinical trials

– Mean time for rash resolution → 3 months

– Drug use may exacerbate prior eczema condition

– May require topical or systemic corticosteroids

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016.

21

Daclizumab does have a black box warning for

hepatic injury because it has been shown to

cause hepatic failure and autoimmune hepatitis.

It can occur at any time during treatment and

there have been cases reported up to four

months after the last dose was given. In fact,

LFT elevations was one of the most commonly-

reported discontinuation reasons in clinical

trials. It’s important to note that this therapy is

contraindicated if patients have any kind of pre-

existing hepatic disease or impairment.

Just like with our other monoclonal antibodies, daclizumab also comes with a REMS program called the Zinbryta REMS program. It does mandate that lab work must be completed at baseline, monthly during therapy, and up to six months after the last dose is given.

Daclizumab also has a black box warning when it

comes to immune-mediated disorders. This can

be a single organ or a systemic, multi-organ

reaction that may require either a corticosteroid

or other immunosuppressant treatment to keep

at bay. Discontinuation may also be warranted.

With that, this concludes my portion of the CE. I’m going to go ahead and turn it over to Aimee.

4141

Daclizumab• Hepatic Injury (Black Box Warning)

– Hepatic failure or autoimmune hepatitis– May occur at any time during treatment

• Cases have been reported up to 4 months after last dose

– ↑ LFTs one of the most common reasons for discontinuation

– Contraindicated if pre-existing hepatic disease or impairment

• Zinbryta REMS Program– Routine lab work MUST be completed– LFTs at baseline, monthly during therapy and x 6

months after last dose

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc 2016

4141

Daclizumab• Hepatic Injury (Black Box Warning)

– Hepatic failure or autoimmune hepatitis– May occur at any time during treatment

• Cases have been reported up to 4 months after last dose

– ↑ LFTs one of the most common reasons for discontinuation

– Contraindicated if pre-existing hepatic disease or impairment

• Zinbryta REMS Program– Routine lab work MUST be completed– LFTs at baseline, monthly during therapy and x 6

months after last dose

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc 2016

4242

Daclizumab

• Immune-mediated disorders (Black Box Warning)

– Lymphadenopathy, noninfectious colitis, and various skin reactions

– Single organ or systemic multi-organ reaction

– May require systemic corticosteroid or other immunosuppressant treatment

– May warrant therapy discontinuation

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016

4242

Daclizumab

• Immune-mediated disorders (Black Box Warning)

– Lymphadenopathy, noninfectious colitis, and various skin reactions

– Single organ or systemic multi-organ reaction

– May require systemic corticosteroid or other immunosuppressant treatment

– May warrant therapy discontinuation

Zinbryta [package insert]. North Chicago, IL: AbbVie Inc, 2016

22

Thank you, Brandon, for the thorough overview

of our disease-modifying therapies. Again, my

name is Aimee Banks. I’m one of the other

clinical pharmacists with the Vanderbilt Specialty

Pharmacy and like Brandon, my practice site is

actually within the Multiple Sclerosis Clinic here

at Vanderbilt. I think that it is important to note:

that we come from a background of a dispensing

pharmacy, specialty pharmacy, but also have

experience and practice in the clinic setting with

face-to-face physician and patient interactions.

Just like Brandon, I have no commercial or

financial relationships to disclose.

I’d like to start off with a chart that just gives an

overview and a comparison of the efficacy data

that was presented previously. I would like to

note that these are all individual trials versus

placebo, with the exception of alemtuzumab

and daclizumab. Those were compared against

an interferon therapy, but these were the

clinical trials that led to FDA approval of these

therapies. These are different patient

populations. Comparison from one trial to the

next is not completely appropriate, but with the

lack of head-to-head data or much head-to-

head data, sometimes this is the best we have.

You can see the interferon class has similar reduction in relapse rates, disability progression, as well as MRI outcomes. We classify those as moderate efficacy, with low-to-moderate toxicity. And then, glatiramer, similar efficacy to the interferons with relapse rate reduction, but either no significant difference or no difference at all with disability progression. Then, as we move into the oral therapies, they appear to be somewhat higher in efficacy compared to the older platform therapies, but they do often come with a higher toxicity profile. Then, the monoclonal antibodies, including natalizumab, alemtuzumab and daclizumab, are going to be our higher, or most highly efficacious therapies, but again, with a higher toxicity profile.

4343

Faculty

Aimee M. Banks, PharmD, BCPSClinical Pharmacists




Disclosure: Dr. Banks has no relevant commercial and/or financial


4343

Faculty

Aimee M. Banks, PharmD, BCPSClinical Pharmacists




Disclosure: Dr. Banks has no relevant commercial and/or financial


4444

Drug Name Trade

Name

versus Reduction

in ARR

Reduction in

CDP

Reduction in MRI

outcomes

Efficacy

Category

Toxicity

Category

IFN beta-1b Betaseron placebo 34% 29%* up to 83% Moderate Low/Mod

IFN beta-1a IM Avonex placebo 32% 37% up to 33% Moderate Low/Mod

IFN beta-1a SubQ Rebif placebo 32% 30% up to 78% Moderate Low/Mod

PegIFN-beta-1a Plegridy placebo 36% 38% up to 67% Moderate Low/Mod

Glatiramer 20 mg Copaxone placebo 29% 12%* not reported Low/Mod Low

Glatiramer 40 mg Copaxone placebo 34% no difference up to 45% Low/Mod Low

Fingolimod Gilenya placebo 54% 30% up to 82% High Mod/High

Teriflunomide Aubagio placebo 32% 30% up to 80% Moderate Moderate

Dimethyl fumarate Tecfidera placebo 53% 40% up to 90% Moderate Moderate

Natalizumab Tysabri placebo 68% 42% up to 92% High High

Alemtuzumab Lemtrada Rebif 55% 42% up to 63% High High

Daclizumab Zinbryta Avonex 45% 20%* up to 54% High High

ARR: annualized relapse rate; CDP: confirmed disability progression* Not statistically significant; % reported as relative risk reduction

4444

Drug Name Trade

Name

versus Reduction

in ARR

Reduction in

CDP

Reduction in MRI

outcomes

Efficacy

Category

Toxicity

Category

IFN beta-1b Betaseron placebo 34% 29%* up to 83% Moderate Low/Mod

IFN beta-1a IM Avonex placebo 32% 37% up to 33% Moderate Low/Mod

IFN beta-1a SubQ Rebif placebo 32% 30% up to 78% Moderate Low/Mod

PegIFN-beta-1a Plegridy placebo 36% 38% up to 67% Moderate Low/Mod

Glatiramer 20 mg Copaxone placebo 29% 12%* not reported Low/Mod Low

Glatiramer 40 mg Copaxone placebo 34% no difference up to 45% Low/Mod Low

Fingolimod Gilenya placebo 54% 30% up to 82% High Mod/High

Teriflunomide Aubagio placebo 32% 30% up to 80% Moderate Moderate

Dimethyl fumarate Tecfidera placebo 53% 40% up to 90% Moderate Moderate

Natalizumab Tysabri placebo 68% 42% up to 92% High High

Alemtuzumab Lemtrada Rebif 55% 42% up to 63% High High

Daclizumab Zinbryta Avonex 45% 20%* up to 54% High High

ARR: annualized relapse rate; CDP: confirmed disability progression* Not statistically significant; % reported as relative risk reduction

23

This illustration is just a visual to compare

efficacy versus toxicity. As you can see, we would

love to have therapy options in the top left

quadrant of this graph with high efficacy and low

toxicity, but currently, we do not have a therapy

that meets that criteria. So, you can see the

trend as toxicity increases.

Let’s look at efficacy on the left-hand side. As efficacy increases in the natalizumab, alemtuzumab, fingolimod category, that comes often times with a trade-off of higher toxicity, as well. Patients with highly active disease or risk

factors for poor prognosis, that may be the best treatment option for those patients. Or on the other spectrum, glatiramer, although not as highly efficacious as the other therapies, has the most benign therapy. Sometimes that is our first-line choice of therapy for patients who present with relatively mild disease, little-to-no risk factors for poor prognosis and maybe are a little bit skeptical of some of the side effect profiles of the other therapies.

Just to touch on pregnancy and MS. Again, as

was mentioned by Dr. Derwenskus in the first

module of this series—which I would

recommend if you haven’t had a chance to

listen to that yet—the onset of MS is most

often in the 20s, 30s and 40s. It does affect

women more than men. With young female

patients, pregnancy is often necessary to

discuss, either their potential for pregnancy or

maybe they are planning to conceive or maybe

they become pregnant while they’re on

therapy. We get questions quite a bit about

pregnancy categories.

You can see that most of the disease-modifying therapies are Category C based on their package labeling. The exception is going to be glatiramer acetate, which is a Category B. It seems to be the safest in pregnancy. As Brandon mentioned, teriflunomide is Category X, so it is contraindicated in patients who are pregnant, or patients who have the potential for pregnancy. If they are not using reliable contraception, it is contraindicated. That is for women as well as men.

4545

Efficacy/Toxicity Illustration

Toxicity*Low Toxicity High Toxicity

High Efficacy

Low Efficacy

Efficacy* ------------------------------------------------------------------------------------------------

----

----

----

----

----

----

----

----

----

----

----

----

----

---

Interferons

Glatiramer

Fingolimod

Dimethyl Fumarate

Teriflunomide

Alemtuzumab

Daclizumab

Natalizumab

*not to scale

4545

Efficacy/Toxicity Illustration

Toxicity*Low Toxicity High Toxicity

High Efficacy

Low Efficacy

Efficacy* ------------------------------------------------------------------------------------------------

----

----

----

----

----

----

----

----

----

----

----

----

----

---

Interferons

Glatiramer

Fingolimod

Dimethyl Fumarate

Teriflunomide

Alemtuzumab

Daclizumab

Natalizumab

*not to scale

4646

Pregnancy and MSCategory B

Glatiramer acetate

Category C

Interferons

Fingolimod*

Dimethyl fumarate*

Natalizumab*

Alemtuzumab

Category X

Teriflunomide*

No adequate data

Daclizumab*

In GENERAL…

• Pregnancy often induces remission

• DMT should be stopped prior to planned conception

• DMT should be stopped once unplanned pregnancy is confirmed

• DMT should be resumed immediately postpartum or after exclusive breastfeeding

*Pregnancy registry available/encouragedHoutchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol. 2013. 260: 1202-1214.

4646

Pregnancy and MSCategory B

Glatiramer acetate

Category C

Interferons

Fingolimod*

Dimethyl fumarate*

Natalizumab*

Alemtuzumab

Category X

Teriflunomide*

No adequate data

Daclizumab*

In GENERAL…

• Pregnancy often induces remission

• DMT should be stopped prior to planned conception

• DMT should be stopped once unplanned pregnancy is confirmed

• DMT should be resumed immediately postpartum or after exclusive breastfeeding

*Pregnancy registry available/encouragedHoutchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol. 2013. 260: 1202-1214.

24

Daclizumab is in a class of its own because the FDA changed their labeling, or their categorization for pregnancy categories. It does not have adequate data in human studies, although it has shown risk in animal populations. That is most in line with Category C, in my opinion. But in general, pregnancy induces remission for patients. Most of the time, it is recommended that the therapy would be discontinued if a patient were trying to conceive or when they do become pregnant. Sometimes that’s not an option if the patient has very aggressive disease, but for the most part, the disease-modifying therapies are not necessary during pregnancy. If the patient were to become pregnant while on a therapy, it’s important to know the pregnancy category and it’s definitely important to suggest that they call their MS clinician immediately for guidance on how to proceed.

Looking at the different dosage forms of the

therapies, this chart just gives kind of an

overview of what dosage forms are available,

specifically with the injectable therapies. It’s

important for patients to be aware that there

are a couple of options. Each drug most often

comes in two different dosage forms, or at least

two different mechanisms for injection.

The difference is going to be if it is in a pre-filled syringe or an autojector type pen device that is prefilled, or if they would need to use the autoject device with the prefilled syringe to turn

that syringe into more of an autojector device. Like with glatiramer acetate, it only comes in a prefilled syringe, but they could use the autoject device if they wanted to. However, PegIFN beta-1a or Plegridy, actually comes separately as a prefilled syringe or a pen. The patient would need to choose which one they preferred so that they can obtain injection training on that specific device. Of note, the beta interferon-1b, Extavia, is dispensed in a kit. It’s a powder vial. It must be reconstituted, but it does come with a full kit that has the powder vial, the diluent as well as the needles and syringes that are necessary for mixing and administration. That is different from the beta interferon-1a intramuscular, which is available in a powder vial. It does not come with the supplies necessary for injection, so those would need to be supplied separately. With dimethyl fumarate, again, it’s a controlled release or delayed release capsule. We’ll talk about that in detail, but it does need to be swallowed whole.

4747

Dosage FormsPre-FilledSyringe

Pens Powder Vials

Autoinject Device

Oral Tablet

Oral Capsule

Glatiramer acetate X X

IFN beta-1a SubQ X X X

IFN beta-1a IM X X Xa

IFN beta-1b Xb X

PegIFN beta-1a X X

Daclizumab X

Teriflunomide X

Dimethyl Fumarate Xc

Fingolimod X

areconstitution supplies not included breconstitution supplies provided in kit cdelayed release

4747

Dosage FormsPre-FilledSyringe

Pens Powder Vials

Autoinject Device

Oral Tablet

Oral Capsule

Glatiramer acetate X X

IFN beta-1a SubQ X X X

IFN beta-1a IM X X Xa

IFN beta-1b Xb X

PegIFN beta-1a X X

Daclizumab X

Teriflunomide X

Dimethyl Fumarate Xc

Fingolimod X

areconstitution supplies not included breconstitution supplies provided in kit cdelayed release

25

For storage requirements, most of the

interferons—well, most of the injectables for

that matter—should be stored in refrigerated

temperatures, but the package labels do include

allowable temperature excursions if necessary.

If a patient is going to travel, maybe they travel

regularly for work or they’re going to go on

vacation, it is suggested that they travel with

their medication cooled in a cooler, but it’s not

completely necessary so long as they can travel

and ensure that it stays at room temperature.

Most of the therapies are stable at room temperature for up to one month with the exception of the beta interferon-1a intramuscular, prefilled syringes and pens. Those are only stable at room temperature for up to seven days.

The oral agents, as well as beta interferon-1b,

are dispensed at room temperature and

should be stored at room temperature. Again,

the beta-1b is a powder that has to be

reconstituted, so the powder is stable at room

temperature. Once it’s reconstituted, it needs

to be injected immediately, but it can be

stored in a refrigerator for up to three hours

prior to injection if that’s necessary.

Dimethyl fumarate specifically says that it should be dispensed in the original container. It should be protected from light and it should be discarded after the bottle is opened after

90 days.

4848

Storage Requirements• Refrigeration preferred, but temp excursions allowed

– Glatiramer acetate• Room temperature up to 1 month

– IFN beta-1a IM• PFS/Pens: room temperature up to 7 days• Unreconstituted powder vial: room temperature up to 30 days• Reconstituted vial: refrigeration up to 6 hours

– IFN beta-1a SubQ• Room temperature up to 30 days

– PegIFN beta-1a SubQ• Room temperature up to 30 days (does NOT have to be

consecutive)

– Daclizumab• Room temperature up to 1 month

4848

Storage Requirements• Refrigeration preferred, but temp excursions allowed

– Glatiramer acetate• Room temperature up to 1 month

– IFN beta-1a IM• PFS/Pens: room temperature up to 7 days• Unreconstituted powder vial: room temperature up to 30 days• Reconstituted vial: refrigeration up to 6 hours

– IFN beta-1a SubQ• Room temperature up to 30 days

– PegIFN beta-1a SubQ• Room temperature up to 30 days (does NOT have to be

consecutive)

– Daclizumab• Room temperature up to 1 month

4949

Storage Requirements

• Room Temperature preferred:

– IFN beta-1b SubQ

• Following reconstitution, may refrigerate for up to 3hrs

– Teriflunomide

– Fingolimod

– Dimethyl Fumarate

• Protect from light

• Store in original container; discard after 90 days

4949

Storage Requirements

• Room Temperature preferred:

– IFN beta-1b SubQ

• Following reconstitution, may refrigerate for up to 3hrs

– Teriflunomide

– Fingolimod

– Dimethyl Fumarate

• Protect from light

• Store in original container; discard after 90 days

26

Just a reminder for most injectables, the

locations that are suggested for an

intramuscular injection, as well as the

subcutaneous injections are provided. Always

read the package label for each specific

product to verify which sites are indicated for

each therapy.

Key points to go over with injectable therapy.

This is really important. A lot of times,

patients are prescribed an injectable therapy

at the time of a new diagnosis. Not only are

they kind of going through the shock of the

diagnosis, but also if they’re told for the first

time that they’re going to need to inject a

therapy, then that can be a shocking

realization.

Sometimes this is our biggest barrier, just to comfort a patient and help them feel comfortable with performing the self-injection, or counseling their caregiver that

may be giving the injection to them; just letting them know what to expect, how to prevent injection site reactions as much as possible and how to manage and treat those. We spend quite a bit of time going over proper injection technique, but most importantly, I would say the patients, they benefit greatly when they’re enrolled in the manufacturer’s support program. Each of the manufacturers has nurse trainers that can meet with the patient once they receive their medication and specifically train them on that therapy with their own devices. We much appreciate our manufacturers for those support programs. It’s really helpful for patients to have that training once their medication has been shipped to them and they have it in-hand. I’ll just touch on some key injectable counseling points. Always tell the patient to wash their hands and clean the injection site prior to the injection. It’s important to rotate the sites, even within one site. Maybe a patient cannot manipulate a syringe or even an autojector device to inject in the back of their arm. Maybe they’re limited to their abdomen and their thighs. They still have plenty of surface area even in those sites that they can inject and rotate the sites. They would want to avoid any areas of lipoatrophy. That’s going to be one of the more common side effects with glatiramer specifically. They should not inject in areas of lipoatrophy or in areas that are visibly irritated or

5151

Brandes DW et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009 Jan;25(1):77-92.Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs 2005;19(3):239-52Subei AM, Ontaneda D. Risk mitigation strategies for adverse reactions associated with the disease-modifying drugs in multiple Sclerosis. CNS Drugs 2015 Sep;29(9):759-71

Administration Key Points: Injectables

• Ensure proper injection technique– Utilize Nurse trainers provided by manufacturer

programs

• Wash hands/clean injection site

• Rotate injection sites

• Avoid areas of lipoatrophy and areas that are irritated, bruised, infected, scarred

• Allow medication to warm to room temperature

• Confirm adequate needle penetration into the SubQ/IM tissue versus intradermally

5151

Brandes DW et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009 Jan;25(1):77-92.Galetta SL, Markowitz C. US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles. CNS Drugs 2005;19(3):239-52Subei AM, Ontaneda D. Risk mitigation strategies for adverse reactions associated with the disease-modifying drugs in multiple Sclerosis. CNS Drugs 2015 Sep;29(9):759-71

Administration Key Points: Injectables

• Ensure proper injection technique– Utilize Nurse trainers provided by manufacturer

programs

• Wash hands/clean injection site

• Rotate injection sites

• Avoid areas of lipoatrophy and areas that are irritated, bruised, infected, scarred

• Allow medication to warm to room temperature

• Confirm adequate needle penetration into the SubQ/IM tissue versus intradermally

5050

Administration – Self Injectables

SubQ

Arms

Abdomen

Thighs

HipsIM

Upper Arm

Upper Thigh

5050

Administration – Self Injectables

SubQ

Arms

Abdomen

Thighs

HipsIM

Upper Arm

Upper Thigh

27

bruised, certainly not infected or scarred. From a comfort standpoint, they should allow their medication to warm up to room temperature. It would just feel a little bit more comfortable upon injection. Then, confirming adequate needle penetration into the correct tissue is important. That’s why it’s helpful to have the nurse trainer there on-site at the time that the patient does their first injection so that they can be certain that the needle depth is set properly.

Administration of the oral therapies is just as

important as with the injectables, specifically

with fingolimod and teriflunomide. These are

both labeled as hazardous agents. That is due to

their pregnancy category and potential for

teratogenicity. Unless it’s the patient handling

their own pills, a family member or a caregiver

really should use gloves if they’re going to be

handling these therapies.

For fingolimod, we do a lot of counseling on how important adherence is. As Brandon mentioned, there is a first dose observation that

is required. That can be logistically complicated for a lot of patients to get to the point of that first dose observation after they’ve had their baseline testing completed. They may have to take off work to sit in a neurology or cardiology clinic for several hours. Once they start on therapy, we want to make sure that they’re aware that it’s very important that they not miss more than the allowed doses. Otherwise, they would have to be considered treatment-naïve and go back through the first dose observation. The first 14 days is the most critical timeframe. They should not miss even one dose in the first 14 days. After that, in weeks three and four, completing the first month, after the first 14 days, they cannot miss seven consecutive days in a row and then, after they’ve been on therapy for one month, they would have to miss 14 consecutive days to be considered treatment-naïve. Fourteen days sounds like a long time to be without such an important therapy, but especially in January and February, in the time of insurance changes and formulary changes, it is not uncommon for patients to be at-risk of being without their medication for that long. They definitely need to be aware of the potential outcome or consequences if they do miss too many doses. They also need to be counseled on the appropriate contacts to reach out to if they are at-risk: their neurologist or MS

5252

Tecfidera [package insert]. Cambridge, MA: Biogen Inc. 2016Gilenya [package insert]. East Hanover, NJ: Novartis Corp 2016Aubagio [package insert]. Cambridge, MA: Genzyme Corp 2016

Administration Key Points: Orals• Fingolimod

– “Hazardous agent” → use gloves– Strict adherence required for first 2 weeks

• Repeat FDO if 1 day missed in first 2 weeks -or- if 7 consecutive days missed during weeks 3 or 4 -or- if 14 consecutive days, after 1st month

• Teriflunomide– “Hazardous agent” → use gloves– Half life: 18 days

• May accelerate elimination w/ cholestyramine or activated charcoal

• Dimethyl fumarate– Delayed-Release (DR) capsule

• Do not crush/chew/open/sprinkle

– Take with food

5252

Tecfidera [package insert]. Cambridge, MA: Biogen Inc. 2016Gilenya [package insert]. East Hanover, NJ: Novartis Corp 2016Aubagio [package insert]. Cambridge, MA: Genzyme Corp 2016

Administration Key Points: Orals• Fingolimod

– “Hazardous agent” → use gloves– Strict adherence required for first 2 weeks

• Repeat FDO if 1 day missed in first 2 weeks -or- if 7 consecutive days missed during weeks 3 or 4 -or- if 14 consecutive days, after 1st month

• Teriflunomide– “Hazardous agent” → use gloves– Half life: 18 days

• May accelerate elimination w/ cholestyramine or activated charcoal

• Dimethyl fumarate– Delayed-Release (DR) capsule

• Do not crush/chew/open/sprinkle

– Take with food

28

clinician or the manufacturer’s support program for a temporary supply possibly to get them through that timeframe. Another point with teriflunomide, or Aubagio, again, it has a very long half-life, so patients need to be aware that if they have side effects with this medication and then they stop therapy, the side effects may not go away because the active metabolites of teriflunomide could be measurable in their system for six months or even 12 months or longer after their last dose. Sometimes an accelerated elimination is required with cholestyramine or activated charcoal. Then again, dimethyl fumarate, which I mentioned before, is a delayed-release capsule. They should not crush it, chew it, or break it open. Certainly don’t sprinkle it on their applesauce or their yogurt. Dimethyl fumarate should always be taken with food, as Brandon mentioned, as well. I tell patients if they remember one thing that I go over with the dimethyl fumarate, it is to always take their capsule after a full meal.

Back to the patient case that Brandon presented

at the beginning of the presentation. What are

some key counseling points? Remember TK was

diagnosed with relapsing remitting MS and her

neurologist is going to be prescribing an

interferon therapy. What counseling points

come to mind when you think about

interferons?

We definitely want to go over possible side effects and mitigation strategies for those side effects. That will be outlined in further detail in the MS103 module that will be available shortly.

Flu-like symptoms, injection site reactions, depression; we want to make sure the patients are aware that if their mood changes or if they feel like they’re depressed or more anxious after they start on therapy, that they contact the appropriate representatives from their doctor’s office or the manufacturer’s support programs or let the pharmacist know so they can reach out and consult with the physician. We want to go over storage requirements, as well as lab requirements and monitoring parameters. Again, the recommended monitoring parameters for interferons are going to be liver function tests, as well as a complete blood cell count specifically with a differential so that the physician or the provider can monitor for possible hepatotoxicity and possible leukopenia.

5353


• Flu-like symptoms and mitigation strategies

• Depression screening/awareness

• Proper administration/injection techniques

• Storage requirements

• Lab requirements

What are the recommended monitoring parameters for interferon?

• LFTs

• CBC + differential

Back to your patient TK…

5353


• Flu-like symptoms and mitigation strategies

• Depression screening/awareness

• Proper administration/injection techniques

• Storage requirements

• Lab requirements

What are the recommended monitoring parameters for interferon?

• LFTs

• CBC + differential


29

Two years later, TK has done well on her

interferon. She has not had any relapses until

the last three months. Now a new MRI shows

two new and active lesions. Also, she’s not fully

recovered from this exacerbation. Her

neurologist would like to change her therapy to

a non-interferon disease-modifying therapy, so

which DMTs are now indicated for TK’s

relapsing-remitting MS?

Let’s talk about MS treatment guidelines.

Unfortunately, or fortunately I guess, depending

on who you ask, we do not have any universally

or widely accepted treatment guidelines for

multiple sclerosis. There are draft proposals in

progress at both the American and the European

Academies of Neurology, but currently we do not

have treatment guidelines.

Why is that the case? As Dr. Derwenskus

detailed previously, it’s a very complex

diagnosis. It includes clinical and radiographic

assessments. Patients present very differently, as

well as their disease course can be variable.

Some patients have a very benign course and

may go decades without really much progression

to disability. Some patients have many relapses

very quickly and progress to the disability more

quickly.

Then, since we don’t have a lot of head-to-head trials comparing the different therapies, it’s hard

to say which drug is going to be first-line, second-line or reserved for salvage treatment.

5656

But why ???

• Complex diagnosis

– Clinical

– Radiographic

• Significant variability

– Presentation

– Disease course

• Poor predictability

• Limited head-to-head data

5656

But why ???

• Complex diagnosis

– Clinical

– Radiographic

• Significant variability

– Presentation

– Disease course

• Poor predictability

• Limited head-to-head data

5454

2 years later…TK has done well on interferon therapy with no relapse symptoms until 3 months ago. A new MRI shows 2 new and active lesions. She has not fully recovered from this exacerbation.

Her neurologist would like to change TK’s therapy to a non-interferon DMT.

Which DMTs are now indicated for TK’s relapsing-remitting MS?

5454

2 years later…TK has done well on interferon therapy with no relapse symptoms until 3 months ago. A new MRI shows 2 new and active lesions. She has not fully recovered from this exacerbation.

Her neurologist would like to change TK’s therapy to a non-interferon DMT.


5555

Current MS Treatment Guidelines

Draft proposals are currently in progress by both American Academy of Neurology (AAN)

and European Academy of Neurology (EAN)

5555

Current MS Treatment Guidelines

Draft proposals are currently in progress by both American Academy of Neurology (AAN)

and European Academy of Neurology (EAN)

30

To reiterate how complex this is, I wanted to

point out this statement by the MS Coalition.

They’re just highlighting that the factors that a

clinician considers when choosing therapy is

very complex and it should definitely be a

discussion with the individual, as well as their

clinician, to determine the best treatment due to

the significant variability in the population.

That was also acknowledged by an expert

opinion paper from the National MS Society’s

Clinical Advisory Board. Again, they just state

how complex the process is, how complex the

patient population is and that it should really

be a discussion between the individual and

their neurologist and that really, because we

don’t have first-, second-, third-line agents

explicitly outlined in treatment algorithms or

treatment guidelines, all agents should be

available so that the clinician can choose the

most appropriate therapy in consultation with

the patient.

How does an MS clinician determine which

therapy to start? It’s very complicated, as I’ve

mentioned before. Probably first and foremost,

they’re going to need to determine what the

diagnosis is. If it’s a relapsing form of MS, we

have treatment options. They’re going to want

to look and see if the patient presents with

aggressive disease or has risk factors for poor

prognosis. They want to look at other disease

states and comorbidities. What are the baseline

labs? What are the other medications that a

patient is taking?

5858

National MS Society’s National Clinical Advisory Board (2008)• Expert opinion paper

• “The Society recognizes that the factors that enter into a decision to treat are complex and best analyzed by the individual patient’s neurologist… All of these FDA-approved agents should be included in formularies and covered by third party payers so that physicians and patients can determine the most appropriate agent on an individual basis; failure to do so is unethical and discriminatory.”

5858

National MS Society’s National Clinical Advisory Board (2008)• Expert opinion paper

• “The Society recognizes that the factors that enter into a decision to treat are complex and best analyzed by the individual patient’s neurologist… All of these FDA-approved agents should be included in formularies and covered by third party payers so that physicians and patients can determine the most appropriate agent on an individual basis; failure to do so is unethical and discriminatory.”

5959

Diagnosis?

Risk for aggressive

course/poor prognosis?

Pregnancy potential?

Insurance formulary?

Patient preference? Compliance concerns?

Previous DMT therapy?

Comorbidities?

Lab abnormalities?

Medications?

DMT selection

considerations

5959

Diagnosis?

Risk for aggressive

course/poor prognosis?

Pregnancy potential?

Insurance formulary?

Patient preference? Compliance concerns?

Previous DMT therapy?

Comorbidities?

Lab abnormalities?

Medications?

DMT selection

considerations

5757

MS Coalition (2014)

• “The factors affecting choice of therapy at any point in the disease course are complex and most appropriately analyzed and addressed collaboratively by the individual and his or her treating clinician… Due to significant variability in the MS population, people with MS and their treating clinicians require access to the full range of treatment options.”

5757

MS Coalition (2014)

• “The factors affecting choice of therapy at any point in the disease course are complex and most appropriately analyzed and addressed collaboratively by the individual and his or her treating clinician… Due to significant variability in the MS population, people with MS and their treating clinicians require access to the full range of treatment options.”

31

These are all things that may exclude certain therapies, more than it would indicate certain therapies. This is really helping eliminate therapy choices and narrow down to the best choice for the patient. If the patient is treatment-naïve versus if they’ve been on previous therapy, that’s going to play a factor into the selection. If a patient is of pregnancy potential or especially the young female patients, if it’s a possibility that they could become pregnant or especially if they’re planning pregnancy, that’s going to limit our treatment options. Patient preference is really important, specifically patients who are strongly leaning towards or discouraged by certain therapies. If a patient comes in and in their mind that they cannot or will not inject themselves, it’s probably not best to prescribe an injectable therapy because they may not be compliant with it. Now with a lot of counseling and encouragement, they may be willing to give it a try, but sometimes patient preference plays even more of an important role than some of the other considerations. Then, as much as we would like to not think that therapy is selected by the insurance companies, unfortunately insurance formularies may play a role in the selection of the therapy, as well.

Briefly, these are some of the risk factors for

poor prognosis or signs of aggressive MS.

Older age at onset, male gender, African-

American ethnicity, the location of the lesion

at diagnosis could be a risk factor for poor

prognosis. If a patient has two or more

attacks in the first two years or if they don’t

completely recover from an attack, which can

be a sign of more aggressive disease or poor

prognosis.

6060

Risk Factors for Aggressive MS Disease Course or Poor Prognosis• Age 40+ at onset

• Male gender

• African American

• Motor, sphincter, cerebellar, spinal cord symptoms

• Brain-stem or spinal-cord lesions at onset

• 2+ attacks in first 2 years of onset

• Incomplete recovery from relapse

Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.

6060

Risk Factors for Aggressive MS Disease Course or Poor Prognosis• Age 40+ at onset

• Male gender

• African American

• Motor, sphincter, cerebellar, spinal cord symptoms

• Brain-stem or spinal-cord lesions at onset

• 2+ attacks in first 2 years of onset

• Incomplete recovery from relapse


32

This is a table just giving more details on

those definitions. It’s much more detailed

than really what’s necessary for this

presentation, but for your reference, you can

see what is considered aggressive or highly-

active lesions specifically on MRI or certain

EDSS or disability scores that could help

determine if a patient has aggressive disease

at onset.

This is a best practice guideline published by

the International Journal of MS Care in 2014.

I think Ford and colleagues did a great job

giving an overview of the treatment options,

treatment selection as well as outlining how

to initiate therapy, as well as follow up and

monitor that therapy.

I’m going to focus on the middle box, the FDA-approved agents for first-line relapsing-remitting MS. As you can see, they just list them out: injectable therapies, the approved IV therapy natalizumab and the approved oral therapies are listed there. They don’t

necessarily recommend one therapy over the other if a patient is treatment-naïve and does not have risk factors for aggressive disease. They are just stating the therapies that were approved for relapsing-remitting MS as of August 2014. They do go over some baseline safety considerations. Depending on what the liver tests are at baseline, depending on what the white blood cell count is, if the patient has a history of varicella zoster immunity or not, that may help guide selection to certain therapies or help exclude certain therapies from being the best indicated for a patient. But really for the most part, they’re just showing that all of these agents are approved as first-line therapy in a treatment-naïve patient with no risk factors for aggressive disease.

6262

Best Practice Guidelines (IJMCS 2014)

1. Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36. 6262

Best Practice Guidelines (IJMCS 2014)

1. Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.

6161

“Aggressive” defined…


6161

“Aggressive” defined…


33

I like this slide because it outlines

considerations with the patient. Patient

preference for administration method. Will the

patient be compliant with the monitoring? We

would say patients always should benefit from

nursing support services, and they included that

in their consideration. Then, they also go on to

outline initiating the therapy, making sure to

monitor the therapy and monitor the efficacy

based on MRI results, as well as relapse rates.

This algorithm is outlining treatment options

for patients with aggressive onset MS or risk

factors for poor prognosis. You can see in the

middle of the algorithm here, basically they go

to natalizumab. Patients with aggressive onset

or poor prognosis, they suggest natalizumab as

the preferred treatment unless the JCV

antibody titer comes back with a high positive

or a positive value that would indicate that the

risk for PML outweighs the benefit of the

therapy.

Tysabri would be preferred for poor prognosis or aggressive onset, but if Tysabri is not an option, then they vaguely suggest the next best available or best alternate disease-modifying therapy. The rest of this graph, they are just suggesting lab monitoring, MRI monitoring and follow-up.

6363Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.




34

Here’s another treatment algorithm or therapy

selection approach. This was published by

Sorensen from the MS Center in Denmark. He

and his colleagues suggest that the first-line

therapies for patients are going to be the

interferon and glatiramer, so the platform

agents and then, the newer oral therapies of

dimethyl fumarate and teriflunomide.

Then, if a patient does not do well or has treatment failure of those first-line therapies, they suggest a more aggressive therapy which is listed in the middle section there, or if a patient

has aggressive onset MS or the risk factors for poor prognosis, they recommend those more aggressive treatments as the first-line therapy, so natalizumab, fingolimod and alemtuzumab were listed as the second-line agents, or first-line if aggressive disease. Then, I added at the bottom daclizumab. It was not part of this publication because it was not approved in Denmark at the time. But if this were to be re-published, my opinion is that daclizumab would be included in that section because it is more of a salvage therapy for patients who have failed two previous disease-modifying therapies, just as alemtuzumab. Then, if none of these FDA-approved or approved agents are effective, then third-line therapy would be experimental therapies or immune-suppression, which could be Methotrexate, Cellcept, Rituximab.

Scolding and colleagues in Britain published

their efficacy categories. They suggest Category

1 as the first-line agent for most patients. Again,

they’re including interferon and glatiramer. They

actually include fingolimod in their Category 1

recommendation, along with teriflunomide and

dimethyl fumarate. Then, they recommend to

reserve the monoclonal antibodies for patients

who are treatment-refractory to a Category 1

DMT, or again if they present with highly-active

disease or have risk factors for poor prognosis.

6565

Curr Opin Neurol. 2014

1st line therapy

• IFN

• GA

• DMFa

• Teriflunomidea

2nd line therapy or 1st

line if aggressive MS

• Natalizumab

• Fingolimod

• Alemtuzumabb

• Daclizumabb

3rd line therapy

• Experimental therapies

• Immuno-suppression

aDMF preferred over teriflunomide if high disease activitybReserve for use after natalizumab and fingolimod

Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014; 27(3): 246-259.

6565

Curr Opin Neurol. 2014

1st line therapy

• IFN

• GA

• DMFa

• Teriflunomidea

2nd line therapy or 1st

line if aggressive MS

• Natalizumab

• Fingolimod

• Alemtuzumabb

• Daclizumabb

3rd line therapy

• Experimental therapies

• Immuno-suppression

aDMF preferred over teriflunomide if high disease activitybReserve for use after natalizumab and fingolimod

Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014; 27(3): 246-259.

6666

Pract Neurol. 2015

• 1st line for most patients

• IFN, GA, Fingolimod, Teriflunomide, DMF

Moderate Efficacy

(Category 1)

• 2nd line if treatment refractory with Category 1 DMT

• 1st line if highly active disease or risk for poor prognosis

• Natalizumab, Alemtuzumab (Daclizumab)

High Efficacy

(Category 2)

Scolding N et al. Association of British Neurologists revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Pract Neurol. 2015; 15: 273–279.

6666

Pract Neurol. 2015

• 1st line for most patients

• IFN, GA, Fingolimod, Teriflunomide, DMF

Moderate Efficacy

(Category 1)

• 2nd line if treatment refractory with Category 1 DMT

• 1st line if highly active disease or risk for poor prognosis

• Natalizumab, Alemtuzumab (Daclizumab)

High Efficacy

(Category 2)

Scolding N et al. Association of British Neurologists revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Pract Neurol. 2015; 15: 273–279.

35

Then, lastly, this is a publication by Ziemssen

and colleagues. Very similar to the previous

article out of Denmark. They include fingolimod

in the more efficacious category with the

monoclonal antibodies, but I like this one

because they show the tolerability switch.

The dotted line here shows that if a patient is started on one therapy, for example, interferons, and does not tolerate the therapy, it is appropriate to switch to another agent in that category of therapies if they don’t have breakthrough disease activity. Assuming that

they are doing well on therapy or their disease is stable, they just cannot tolerate certain side effects, and then it would be appropriate to change therapy within that list of medications. But once they develop disease activity breakthrough, or the therapy has been determined as a treatment failure, then it would be appropriate to move onto a more highly-active therapy. Again, daclizumab was not included in this publication because it wasn’t available at the time.

How do you determine when to switch therapies

or what considerations, what factors should be

considered? Basically efficacy, safety and then,

patient-specific reasons are valid. If the therapy

is just not working, if the patient is having

recurring relapses, if their disability is

progressing, but they’re still having active

relapses, then that would be more of a

secondary progressive with relapses, or

progressive relapsing diagnosis, so changing the

disease-modifying therapy is indicated.

Also, if they don’t appear to be tolerating the therapy or they develop new comorbidities or are prescribed new therapies that have significant drug interactions that would be a reason to change therapy. Specifically with Natalizumab, if they become highly positive for the anti-JCV antibodies, that would be a reason to change to a different therapy. Then, patient-specific factors should be considered, as well. If the patient does not feel as though the therapy if effective, they have a perceived lack of efficacy, that is a very real perception by the patient. It may not be appropriate to continue them on that therapy if they do not feel like it is effective for them because it can oftentimes affect adherence. Those considerations should be included, as well.

6767

Mult Scler Relat Disord. 2015

Ziemssen T et al. Optimizing therapy early in multiple sclerosis: An evidence-based view. Mult Scler Relat Disord. 2015 Sep;4(5):460-469.OPEN ACCESS GRAPHIC via Creative Commons: http://creativecommons.org/licenses/by/4.0/.

(Daclizumab)

6767

Mult Scler Relat Disord. 2015

Ziemssen T et al. Optimizing therapy early in multiple sclerosis: An evidence-based view. Mult Scler Relat Disord. 2015 Sep;4(5):460-469.OPEN ACCESS GRAPHIC via Creative Commons: http://creativecommons.org/licenses/by/4.0/.

(Daclizumab)

6868

Switching DMTs

Reasons to change therapy

• Efficacy– Suboptimal response

• Safety– Risk for or presence of

adverse effects • New comorbidities

• Abnormal labs

• JCV+

• Patient-specific– Poor adherence

– Perceived lack of efficacy

Selection considerations

• Same process as initial DMT selection, plus…

– Address adherence

– Consider DMT with different mechanism

– Consider washout periods


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Switching DMTs

Reasons to change therapy

• Efficacy– Suboptimal response

• Safety– Risk for or presence of

adverse effects • New comorbidities

• Abnormal labs

• JCV+

• Patient-specific– Poor adherence

– Perceived lack of efficacy

Selection considerations

• Same process as initial DMT selection, plus…

– Address adherence

– Consider DMT with different mechanism

– Consider washout periods


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Then, how does the clinician determine which therapy is indicated at the time of the switch? It’s the same factors as we mentioned before, but also including why is the patient changing therapy. If we’re changing for lack of efficacy, maybe we need a therapy with a different mechanism or with a higher efficacy category. If it’s lack of efficacy due to adherence, then maybe switching to a different route of administration. Also considering time between therapy, and washout is important, as well.

To briefly talk about washout periods, in

general, we need to balance the risk of relapse

from being without therapy against the risk of

overlapping side effects and toxicity. For

example, if a patient is on an interferon therapy

and their LFTs increase to four or five times the

upper limit of normal, the interferon therapy

would be discontinued, but it probably would

be best to start a therapy that doesn’t affect the

liver function tests, or wait for the liver function

test to return to a more acceptable value before

starting another therapy such as teriflunomide

that also carries that same risk. Then, with teriflunomide specifically, again, accelerated elimination

may be warranted, specifically if a patient is experiencing side effects or wishes to become

pregnant.

Then, switching from natalizumab to fingolimod, which comes up quite a bit here in our practice, because the patient who is on natalizumab most of the time has highly aggressive disease. If they become JCV-positive at a high level, then they need to switch therapies because of the risk of PML. It’s most often that they’re going to be switched to another therapy with high efficacy. Oftentimes that therapy is fingolimod. Waiting the 10-12 weeks that some insurance companies require before initiating fingolimod therapy may actually cause or put the patient at-risk of increased rebound relapse from the discontinuation of the natalizumab. Especially if a patient has risk factors for highly aggressive disease, they should be switched to fingolimod as suggested by some authors within six-to-eight weeks. Now switching to alemtuzumab, there’s been some discussion by Giovannoni and colleagues that the risk of carryover PML should be considered. There should be a washout period in-between

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Washout Period Proposals• In general: balance overlapping side effects/risks against

risk for relapse1

– washout until lab recovery if abnormal lab and low risk of relapse

• Teriflunomide accelerated elimination may be warranted2

– Cholestyramine or activated charcoal– May confirm with undetectable active metabolites

• Natalizumab → Fingolimod1, 3

– Less than 6 to 8 weeks to reduce rebound relapse• Especially if risk factors for high disease activity

• Natalizumab → Alemtuzumab3

– Consider 6+ months to reduce “carry-over PML”– Consider bridge with alternate DMT to reduce rebound relapse

1. Jokubaitis VG, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology. 2014 Apr 8;82(14):1204-11. 2. Aubagio [package insert]. Cambridge, MA: Genzyme Corp 2016.3. Giovannoni G, et al. Switching patients at high risk of PML from natalizumab to another disease-modifying therapy. Pract Neurol. 2016 Oct;16(5):389-93.

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Washout Period Proposals• In general: balance overlapping side effects/risks against

risk for relapse1

– washout until lab recovery if abnormal lab and low risk of relapse

• Teriflunomide accelerated elimination may be warranted2

– Cholestyramine or activated charcoal– May confirm with undetectable active metabolites

• Natalizumab → Fingolimod1, 3

– Less than 6 to 8 weeks to reduce rebound relapse• Especially if risk factors for high disease activity

• Natalizumab → Alemtuzumab3

– Consider 6+ months to reduce “carry-over PML”– Consider bridge with alternate DMT to reduce rebound relapse

1. Jokubaitis VG, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology. 2014 Apr 8;82(14):1204-11. 2. Aubagio [package insert]. Cambridge, MA: Genzyme Corp 2016.3. Giovannoni G, et al. Switching patients at high risk of PML from natalizumab to another disease-modifying therapy. Pract Neurol. 2016 Oct;16(5):389-93.

37

natalizumab and alemtuzumab so that if PML were to become noticed from natalizumab even after therapy is discontinued, at least they would not be on a long-term immunosuppressant such as alemtuzumab. They suggest an alternate DMT in the 6-12 months’ timeframe between natalizumab and alemtuzumab therapy.

Now back to our patient, TK, who is

discontinuing interferons and needs to change

to a new therapy. What are the current

therapies that are indicated for relapsing-

remitting MS? This is not intended to be a trick

question. These are the therapies that are

actually indicated for relapsing-remitting MS and

excluding the two therapies that are only

indicated as salvage therapies after failure of

two agents.

Since she’s only been on an interferon, she’s only failed basically one therapy. Alemtuzumab

and daclizumab are not indicated, but glatiramer acetate, the three oral therapies, as well as natalizumab are all indicated for her for relapsing-remitting MS. Most clinicians would not go with a less-efficacious therapy, but it is actually still indicated.

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• Glatiramer acetate

• Fingolimod

• Teriflunomide

• Dimethyl fumarate

• Natalizumab

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• Glatiramer acetate

• Fingolimod

• Teriflunomide

• Dimethyl fumarate

• Natalizumab

38

In conclusion, disease-modifying therapies are

used to reduce lesion burden, reduce relapse

rates and disease progression and disability

progression for MS patients. We have several

treatment options available now. They all have

very unique efficacy and safety profiles, but

with a lack of a widely-accepted treatment

guideline, the selection process can be quite

complex and should always be individualized.

Pharmacists and nurses can play a really important role in the treatment for patients by providing education, counseling and helping the

clinician monitor for possible side effects, managing possible side effects or identifying possible sub-optimal efficacy.

That concludes the MS102 presentation. Thank

you for joining us and we hope that you tune in

for the next module, which will detail specific

roles that pharmacists and nurses can play in

optimizing the treatment for MS patients. Thank

you.

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In Conclusion…

• DMTs are indicated to reduce lesion burden, relapse rates, disability progression

• Several treatment options are available with unique efficacy/safety profiles

• Lack of widely accepted treatment guidelines

• DMT selection based on multiple individual factors

• Providing patient education and monitoring is a vital role of both nurses and pharmacists

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In Conclusion…

• DMTs are indicated to reduce lesion burden, relapse rates, disability progression

• Several treatment options are available with unique efficacy/safety profiles

• Lack of widely accepted treatment guidelines

• DMT selection based on multiple individual factors

• Providing patient education and monitoring is a vital role of both nurses and pharmacists

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Continuing Education for this activity is processed through the ProCE online CE Center. To receive CE credit, view the Presentation and/or the Digital Guide Book, then complete the online Post-Test and Evaluation.

Post-Test

1. Which Disease Modifying Therapy (DMT) requires the patient to administer the first dose under observation?

a. Dimethyl Fumarate b. Teriflunomide c. Fingolimod d. Daclizumab

2. The following should be taken into consideration when selecting the most appropriate DMT for a specific patient

a. Pregnancy potential b. Lab abnormalities c. Previous Disease Modifying Therapy

(DMT) d. All of the above

3. Which medication comes in the following formulations: Pre-filled syringe, Pen, and Powder vial?

a. IFN beta-1b b. IFN beta-1a IM c. IFN beta-1a SubQ d. PEGIFN beta-1a

4. The following medication(s) is/ are considered a Limited Distribution Drug (LDD):

a. PEGIFN beta-1a b. Fingolimod c. Glatiramer acetate d. Both A and B

5. The following are risk factors for Natalizumab-induced PML:

a. Prior immunosuppressant therapy b. Presence of anti-JCV antibodies c. Longer treatment duration d. All of the above

6. Patients starting on daclizumab should be appropriately counseled on the potential for an Immediate Post-Injection Reaction (IPIR).

a. True b. False

7. An accelerated elimination protocol with cholestyramine may be appropriate following the discontinuation of which medication?

a. Alemtuzumab b. Dimethyl Fumarate c. Teriflunomide d. None of the above

8. The following medications require routine Liver Function Test (LFT) monitoring during therapy

a. IFN beta-1a SubQ b. Fingolimod c. Glatiramer acetate d. Both A and B e. All of the above

9. Which DMT should be reserved for patients with inadequate response to two or more DMTs?

a. Daclizumab b. Natalizumab c. Fingolimod d. Dimethyl fumarate

10. Which of the following is not a treatment/efficacy goal of the currently available DMTs?

a. Reduce clinical relapses b. Delay progression of disability c. Reduce new/active lesions d. Reverse neurological damage and

disability

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