A CSPE Core Curriculum Seriess3.proce.com/res/pdf/MS-102_DigitalGuideBook.pdf · educational...
Transcript of A CSPE Core Curriculum Seriess3.proce.com/res/pdf/MS-102_DigitalGuideBook.pdf · educational...
A CSPE Core Curriculum Series
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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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MS-102: Navigating the MS Therapeutic Landscape
Aimee M. Banks, PharmD, BCPSBrandon M. Markley, PharmD, BCPS
Clinical PharmacistsVanderbilt University Medical Center
Multiple Sclerosis ClinicNashville, Tennessee
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MS-102: Navigating the MS Therapeutic Landscape
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
Multiple Sclerosis ClinicNashville, Tennessee
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
relationships to disclose.
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Faculty
Brandon M. Markley, PharmD, BCPSClinical Pharmacists
Vanderbilt University Medical Center
Multiple Sclerosis ClinicNashville, Tennessee
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
relationships to disclose.
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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?
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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?
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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
• 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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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
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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.
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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.
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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
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.
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
• 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.
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
Gilenya [package insert]. East Hanover, NJ: Novartis Corp, 2016.
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
Gilenya [package insert]. East Hanover, NJ: Novartis Corp, 2016.
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
Gilenya [package insert]. East Hanover, NJ: Novartis Corp, 2016.
2020
Teriflunomide
• Pyrimidine synthesis inhibitor to reduce proliferation of activated lymphocytes in CNS
• Active metabolite of leflunomideMechanism
• Relapsing forms of MSIndication
• ↓ 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
• Relapsing forms of MSIndication
• ↓ 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
Aubagio [package insert]. Cambridge, MA: Genzyme Corp, 2016.
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
Aubagio [package insert]. Cambridge, MA: Genzyme Corp, 2016.
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
Aubagio [package insert]. Cambridge, MA: Genzyme Corp, 2016.
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
Aubagio [package insert]. Cambridge, MA: Genzyme Corp, 2016.
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
Aubagio [package insert]. Cambridge, MA: Genzyme Corp, 2016.
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
• Relapsing forms of MSIndication
• ↓ 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
• Relapsing forms of MSIndication
• ↓ 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
• Relapsing forms of MSIndication
• ↓ 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
• Relapsing forms of MSIndication
• ↓ 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
• Relapsing forms of MSIndication
• ↓ 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
• Relapsing forms of MSIndication
• ↓ 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
Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.
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
Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.
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
Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.
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
Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.
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
• Relapsing forms of MS
• 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
• Relapsing forms of MS
• 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
Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.
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
Lemtrada [package insert]. Cambridge, MA: Genzyme Corp, 2014.
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
Vanderbilt University Medical Center
Multiple Sclerosis ClinicNashville, Tennessee
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. Banks has no relevant commercial and/or financial
relationships to disclose.
4343
Faculty
Aimee M. Banks, PharmD, BCPSClinical Pharmacists
Vanderbilt University Medical Center
Multiple Sclerosis ClinicNashville, Tennessee
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. Banks has no relevant commercial and/or financial
relationships to disclose.
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
What are some key counseling points about interferons to discuss with her?
• 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
What are some key counseling points about interferons to discuss with her?
• 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…
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.
Which DMTs are now indicated for TK’s relapsing-remitting MS?
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
Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
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…
Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
6161
“Aggressive” defined…
Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
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.
6363Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
6464Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
6464Ford 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.
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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.
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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)
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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)
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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
Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
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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
Ford CC, et al. Int J MS Care. 2014. 16(6): 1-36.
36
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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Back to your patient TK…
Which DMTs are now indicated for TK’s relapsing-remitting MS?
• Glatiramer acetate
• Fingolimod
• Teriflunomide
• Dimethyl fumarate
• Natalizumab
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Back to your patient TK…
Which DMTs are now indicated for TK’s relapsing-remitting MS?
• Glatiramer acetate
• Fingolimod
• Teriflunomide
• Dimethyl fumarate
• Natalizumab
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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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MS-102: Navigating the MS Therapeutic Landscape
Aimee M. Banks, PharmD, BCPSBrandon M. Markley, PharmD, BCPS
Clinical PharmacistsVanderbilt University Medical Center
Multiple Sclerosis ClinicNashville, Tennessee
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MS-102: Navigating the MS Therapeutic Landscape
Aimee M. Banks, PharmD, BCPSBrandon M. Markley, PharmD, BCPS
Clinical PharmacistsVanderbilt University Medical Center
Multiple Sclerosis ClinicNashville, Tennessee
39
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