multiple sclerosis: managing the whole...

© 2012 by the American Pharmacists Association. All rights reserved.

Multiple Sclerosis: Managing the Whole Patient

Jacquelyn Bainbridge, PharmD, FCCPProfessor, Department of Clinical Pharmacy and Neurology,

University of Colorado

Ellen Whipple Guthrie, PharmDMedical Advisory Board, MS Foundation

Clinical Assistant Professor, University of Georgia College of Pharmacy

Supported by independent educational grants from

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Elan Pharmaceuticals, Inc., EMD Serono, Inc. and

Genzyme.

Disclosures• Ellen Guthrie, Pharm D declares the following conflicts:

• Medical Communications – Contractor• Teva Neuroscience - Stockholer

• Jacquelyn Bainbridge Pharm.D. declares the following conflicts:• NIH - Research grant funding• TEVA Neurosciences – Honoraria

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• UCB Pharma – Honoraria

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Learning Objectives

• Review the current clinical management of multiple sclerosis (MS) including long-term efficacy and safety of treatment options

• Differentiate new and emerging therapies for MS and discuss the role of the pharmacist in adherence

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• Describe symptoms that are commonly associated with MS and pharmacologic options for managing them

• Discuss the role of biomarkers in MS• Explain strategies for promoting patient adherence,

managing adverse events, and assisting patients with medication administration

Which Drug Used to Treat Multiple Sclerosis Requires a First Dose Observation Period?

0%

0% 1.Dalfampridine2.Glatiramer acetate3

66

0%

0% 3.Fingolimod4. Interferon Beta 1a

EG Reports Severe Flu-Like Symptoms with her Multiple Sclerosis Therapy. Which First Line Drug Would be your Next Choice?

0%

0% 1.Fingolimod2.Glatiramer acetate3

77

0%

0% 3. Interferon Beta 1b4. Interferon Gamma 1a


MB is Experiencing Fatigue and Depression. Which Drug is a Good Option for this Patient?

0%

0% 1.Amitriptyline2.Mirtazapine3

88

0%

0% 3. Imipramine4.Fluoxetine

RP is Complaining of Problems Walking. You Recommend Which of the Following Drugs at add to his Multiple Sclerosis Therapy?

0%

0% 1.Dalfampridine2.Bupropion3

99

0%

0% 3.Modafinil4.Natalizumab

Which Option Below has Proven to Promote Adherence in Multiple Sclerosis Patients

0%

0%

0% 1. Set realistic expectations2. Nonadherence is not a problem3 Give a drug holiday

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0%

0% 3. Give a drug holiday4. Defer the drug copay

The Basics• MS is a chronic inflammatory disease characterized

by myelin destruction and axonal damage• The term multiple sclerosis refers to 2

characteristics of the disease: • The numerous affected areas of the brain and spinal

d d i lti l l i t th t

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cord producing multiple neurologic symptoms that accrue over time

• The characteristic plaques or sclerosed areas that are the hallmark of the disease

MS=multiple sclerosis; Neurology. 2007;68(Suppl 3):S22-S31.

Epidemiology• >400,000 American victims, 2.7 million world wide• 200 new cases of MS are diagnosed each week in the U.S.• MS is the second most common cause of neurologic disability

in the U.S.• 80% develop MS between 16 and 45 years of age• Female to male risk ratio 2.4:1• Outcomes Untreated:

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– 50% of patients require a cane or more support for ambulation within 10 years of onset.

– 30% of patients will become wheelchair or bed bound– Average life span decreased by <5 years

• Health-related costs: $47,215/Pt/yr*• Leading cause of nontraumatic disability in young women and

the second leading cause of disability in young men in US• Suicide is 6 to 7 times more likely than controls

Pharmacotherapy. 2010;30:916-927; American Family Physician. 2004;70:1935-1944. *Neurology. 2006;66:1696-1702

Etiology• The exact cause(s) of MS are not fully understood• Evidence suggests that MS is probably caused by a

combination of factors including:– Genetics– Altered immune system

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– Environmental factors (e.g., measles, mumps, rubella, Epstein-Barr virus, human herpes virus 6)

J Neurol. 2011;258:728-739; Drugs 2008; 68: 2445-2468; NeuroRX 2005;2:638-649.


Multiple Sclerosis

• An immune-mediated disease in genetically susceptible individuals

• Dual nature: inflammatory and neurodegenerative

• Demyelination leads to slower d ti

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nerve conduction• Axonal injury and destruction

are associated with permanent neurologic dysfunction

• Lesions occur in optic nerves, periventricular white matter, cerebral cortex, brain stem, cerebellum, and spinal cord

Drugs 2008; 68: 2445-2468; Neurology. 2007;69:1603-1609; N Engl J Med. 1998;338:278-285.

©2008 Partners Harvard Medical International.

Behavioral Changes

• Vitamin D deficiency associated with risk of MS; not clear if addition to diet alters risk at this point

• Higher vitamin D levels associated with a lower relapse risk

• Smoking increases risk for:

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– Conversion to CDMS, 51% vs 75% at 3 years– Development of MS in general – Development of disability in MS– MRI abnormalities predictive of poor outcome

• Excess body weight associated with risk of MS;– What is the role of weight reduction in changing the

course of the disease?

Munger et al. JAMA 2006;296:2832-2838; Hedstrom et al, Neurology. 2009 ;73:696-701; Zivadinov, R. et al. Neurology. 2009;73:504-510; Munger KL et al, Neurology. 2009; 73:1543-1550.

Diagnosis• There is no single test used to diagnose MS• Diagnosis should be based on history and clinical

findings• Tests used to aid the diagnosis of MS:

– MRI scans

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– Visual evoked potentials– Lumbar puncture (CSF evaluation)– Optic coherent tomography

CSF=cerebrospinal fluid; MRI=magnetic resonance imaging;

J Neurol. 2011;258:728-739; Pharmacotherapy. 2010;30:916-927; Neurology. 2007;68:S46-S53.

Biomarkers in MS

• May be useful in monitoring progression of MS and treatment response instead of clinical end points or current practice

• Monitoring progression– The complement regulator factor H – Allows progressive MS to be distinguished form RRMS

• Monitoring treatment response– The development of neutralizing antibodies (Nabs)

*

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• Accelerated disease progression*– Persistent neutralizing antibodies to interferon beta appears to

accelerate disease progression in some patients– One study showed 24% of patients were Nabs + after 25 months

of stopping the interferon, in patients with persistent Nabs– Associated with:

• Increase in annual relapse rate• Reduction in the time to reach a score of 6 on the Expanded

Disability Status Scale (EDSS)• Increase in the probability of changing to a second-line drug

*Arch. Neurol.2010; 67: 402-407. Nat. Rev. Neurol.2011;7:74-75.

Measuring Neutralizing Antibodies

• IFNß IFNß induced proteins– b2-Microglobulin, Neopterin, TRAIL, myoxvirus resistance

protein A (MxA)

• Binding antibodies (BAb) + IFNß IFNß induced proteins

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• Neutralizing antibodies (NAb) + IFNß ≠ IFNßinduced proteins, therefore; decreased clinical effect of IFNß*

• In Scandinavian countries discontinuation of IFNß and change of therapy is strongly recommended with persistent, moderate, or high NAb titers**

* J Neurol. 2011;258:904-907. **Lancet Neurol 2010;9:740-750

Biomarkers in MS

• Cerebrospinal fluid (CSF)– Oligoclonal bands – CXCL13– IgG synthesis– MRZ reaction +

• Neurodegenerative CSF • Serum

clinically isolated syndrome (CIS) clinically definite MS (CDMS)

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– Autoantibodies against myelin - Anti-MOG (IgG), anti-MBP (myelin basic protein), anti-PLP

• Structural MRI– Gd enhancing lesions, T1, T2, spinal cord, gray and white matter

atrophy, etc.• Single-photon emission computed tomography (SPECT),

Positron emission tomography (PET), Optical coherent tomography (OCT), N-acetyl – aspartate (NAA) , Evoked potentials (EP), Visual evoked potentials (VEP)

Progress in Neurobiology. 2011;95:670-685.


Approach to Multiple Sclerosis Therapy

• Treatment of acute exacerbations

• Modification of disease progression

• Managing symptomatic complications

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Managing symptomatic complications

Case Study (Part I)

• July 2006• TG is a 17 year-old, white female who lives in

Boston• CC: Currently things are blurry in her right eye

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CC Cu e y gs a e b u y e g eye• Normal findings on MRI• Patient’s aunt has MS • Patient diagnosed with optic neuritis and CIS

• How should this patient be managed?

CIS=clinically isolated syndrome; CC=chief compliant; MRI=magnetic resonance imaging

Acute Exacerbations

• Development of focal neurologic deficits along with physical findings for at least 24 hours and 30 days apart from the previous event

• Return to baseline by 3 months• Anti-inflammatory therapies can reduce

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inflammation in brain and spinal cord• There may be relief of signs and symptoms,

including severity and duration• Adrenocorticotropin hormone (ACTH)• Intravenous immunoglobulin (IVIG)

Pharmacotherapy. 2010;30:916-927; Lancet 2002;359:1221-1231.

Treating Exacerbations

• 1st line: corticosteroids.– Methylprednisolone 0.5-1gram IV every day for 3 to 7days

(per American Academy of Neurology).

• 2nd line: IVIG or plasmapheresis. • When should 2nd line treatments be considered?

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– Patient unresponsive to corticosteroids.– Corticosteroids contraindicated (e.g., severe osteoporosis;

brittle diabetes).

Pharmacotherapy. 2010;30:916-927; Lancet 2002;359:1221-1231.

Clinically Isolated Syndrome (CIS)

• A single, symptomatic neurologic episode that is consistent with MS

• Typically the first clinical event to take place among patients with MS

• Symptoms may include optic neuritis ocular motor

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• Symptoms may include optic neuritis, ocular motor syndromes, ataxia, sensory or motor syndromes, partial myelitis, and/or bladder or bowel dysfunction

CDMS• McDonald Criteria:

– Requires the presence of ≥ 2 lesions separated by time and space (allows for MRI scans, CSF, and evoked potential findings to identify second attacks)

– Calls for one of 3 outcomes: • 1) Diagnosis of MS• 2) “Possible” diagnosis of MS

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) g• 3) No diagnosis of MS

• Can be diagnosed on one MRI (MAGNIMS)– Dissemination in time (DIT) – 2 Gd enhancing lesions in

different areas of the brain (one causing symptoms)– Dissemination in space (DIS) – at least 1 T2 lesion in a

least 2 out of 4 areas of the brainCDMS=clinically defined multiple sclerosis; CSF=cerebrospinal fluid; MAGNIMS = European Multicent

Collaborative Research Network on MRI in MSNeurol. 2011;258:728-739; Pharmacotherapy. 2010;30:916-927; Ann Neurol. 2011;69:292-302.Neurology 2010;74, 427-434.


Case Study (Part II)

• August 2006• Patient and neurologist discuss the first-line DMTs• The patients inquires if she will need treatment for

the CIS.

2727CIS=clinically isolated syndrome; DMTs=disease-modifying therapies.

Why Treat CIS?

• 60-80% of patients with CIS who have demyelinating lesions on MRI, eventually develop CDMS

• 20% of patients with normal MRIs develop CDMS• The ultimate goal is to delay disease progression to

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CDMS, through the use of early therapeutic intervention.

Prognosis in CISRate of Conversion to CDMS

80

100

0 Lesionso CD

MS

Baseline Measure

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0

20

40

60

5 10 15

0 Lesions1–3 Lesions4–10 Lesions>10 Lesions

Years

% C

onve

rtin

g to

Adapted with permission from Brex et al. N Engl J Med. 2002;346:158-164.

FDA-Approved Therapies First-line DMTs

DMT Indication Dosage and Administration

GA1 CIS, RRMS 20 mg SQ once daily

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IFNβ-1a IM2 CIS, RRMS 30 mcg IM 1x/week

IFNβ-1a SQ3 RRMS* 22-44 mcg SQ 3x/week

IFNβ-1b4,5 CIS, RRMS 250 mcg SQ every-other day

*FDA expected to add indication for CIS based on results from REFLEX trial. DMTs=disease modifying therapies; GA=glatiramer acetate; IFN=interferon; RRMS=relapsing-remitting multiple sclerosis;

1Product information for Copaxone; 2Product information for Avonex; 3Product information for Rebif; 4Product information for Extavia; 5Product information for Betaseron.

Efficacy in CIS Clinical Studies

Name Agents/Dosing Findings (vs. placebo)PreCISeTrial1

GA 20 mg/day vs. placebo

At 3 years, GA ↓’ed the conversion to CDMS by 45%.

BENEFITTrial2

IFN β-1b 250 mcg every-other day vs.

l b

At 2 years, IFN β-1b ↓’ed the conversion to CDMS by 17%.

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placebo y

CHAMPSTrial3

IFN β-1a 30 mcg 1x/week vs. placebo

At 3 years, IFN β-1a ↓’ed the conversion to CDMS by 15%.

REFLEXTrial4

IFN β-1a 44 mcg 3x/week vs. placebo

At 2 years, IFN β-1a ↓’ed the conversion to CDMS by 51%.

BENEFIT=Betaferon in newly emerging MS for initial treatmentCHAMPS=High-risk subjects Avonex MS prevention study; ETOMS=Early Treatment Of MS;

GA=glatiramer acetate; IFN=interferon; IM=intramuscular; MS=multiple sclerosis; PreCISe = Early GA treatment in delaying conversion to CDMS of subjects presenting with CIS; SQ=subcutaneous;

REFLEX=REbif FLEXible dosing in early MS. 1Lancet.2009;66:841-6; 2Neurology. 2006;67:1242-49; 3N Engl J Med.2000;343:898-904. 5Merck-Serono Press Release, October 2010.

Case Study (Part II-cont)

• Patient decides to not start treatment with a DMT because of “needle phobia”

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Case Study (Part III)

• October 2010• PMH: Optic neuritis resolved with corticosteroids• CC: Patient experiencing severe vertigo• 3 lesions in different areas of the brain are found on

MRI scans

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• Patient diagnosed with MS and agrees to be treated with an injectable DMT

The patient inquires further about the injectable DMTs and asks “if they are all equally effective.”

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IFNβ Products

• 3 formulations (IFNβ -1b SQ, IFNβ -1a IM, and IFNβ -1a SQ)

• Pregnancy Category: C• Drug Interactions: Possibly hepatically active

drugs

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drugs• Laboratory monitoring: CBC, LFT, TSH

Product information for Avonex, Betaseron, Extavia, and Rebif.

IFN-β (Formulations)

• IFN β-1a IM– Low dose IFN-β product– 30 mcg IM every week

• IFN β-1b SQ– High dose IFN-β product

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High dose IFN β product– 250 mcg SQ every other day

• IFN β-1a SQ – High dose IFN-β product– (22 mcg – low dose) to 44 mcg SQ every other day

Product information for Avonex, Betaseron, Extavia, and Rebif.

IFN-β (MOA)

• Does not cross the BBB• Works outside of the CNS to reduce inflammation• Stabilizes the BBB

– Decreases matrix metalloproteinases• No evidence of neuroprotection

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o e de ce o eu op o ec o

BBB=blood brain barrier; Product information for Avonex, Betaseron, Extavia, and Rebif.

IFN-β (Safety)• Menstrual irregularities• Flu-like symptoms• Injection site reactions• Depression

3838Product information for Avonex, Betaseron, Extavia, and Rebif.


IFN-β (Pivotal Trials)

IFN β-1b SQ

Decreased frequency of relapses; more patients free of relapses over a 2-year treatment period1

IFN β-1a IM

CHAMPS: Relative reduction in the volume of brain lesions, fewer new or enlarging lesions, and fewer Gd+ lesions at 18 months; f ti t d l d CDMS 3

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fewer patients developed CDMS over a 3-year follow-up period2

IFN β-1a SQ

PRISMS3/3EVIDENCE4: Decreased frequency of relapses; delayed the accumulation of physical disability

CHAMPS=Controlled High Risk Avonex MultiPle Sclerosis; PRISMS=Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis;

EVIDENCE=EVidence of Interferon Dose-response: European North American Comparative Efficacy; 1Neurology. 1993;43:655-661; 2N Engl J Med. 2000;343(13):898-

904; 3Lancet. 1998;352:1498-1504; 4Lancet .2002;359(9316):1453-1460.

Glatiramer Acetate (GA)

• Dosing: 20 mg SQ every day• Pregnancy Category: B• Drug Interactions: None noted in clinical trials• Laboratory monitoring: None needed

4040Product information for Copaxone.

GA (MOA)

• Not an IFN-β product• Produces T-cells that suppress the immune attack

on myelin• Resembles myelin basic protein• Exerts effect within the BBB

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• Exerts effect within the BBB• Neuroprotective properties

Product information for Copaxone.

GA (Safety)

• Injection site reactions• Hives • Post injection reaction

4242Product information for Copaxone.

GA (Pivotal Trial)

• 251 people with RRMS were randomly received either GA or placebo

• After 2-years, patients who received GA had 29% reduction in ARR, compared to placebo1

• After 15-years, patients who remained in the study

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and received GA experienced stabilized or improved EDSS, and 65% had not yet transitioned to SPMS2

ARR=annualized release rate; RRMS=relapsing-remitting multiple sclerosis; EDSS=Expanded Disability Status Scale; SPMS=secondary-progressive multiple

sclerosis; 1Neurology 1995; 45:1268-1276; 2Press release, The Consortium of Multiple Sclerosis Centers, February 2010.

Case Study (Part IV-cont)

• October 2010• Patient and MD decide on IFN ß-1b SQ 250 mcg

every other day• Pharmacy consult

– Injection training

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– Importance of adherence


Injection Training

• Rotate injection sites• Use an autojector (available at no charge from

manufacturer)• Inject medication at room or body temperature• Ice the area before and after injecting the

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ce e a ea be o e a d a e jec g emedication

• Massage the area before and after injecting the medication

Journal of the American Pharmaceutical Association 2002;42(5):753-766.

Importance of Adherence• Between 17% and 40% of patients stop taking

DMTs within 1 year of initiation• Multifactorial

– Perceived lack of efficacy– AEs– Depression

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• Within 6 months of treatment initiation, 41% of patients had new or increased depression

• Decreased adherence in patients with untreated depression

• 50% of patients on a DMT stopped taking their medications within 4 years of diagnosis*

– 56% of treated and 37% of nontreated patients were employed full time

J Neurol Sci. 2007;259:104-108; Mult Scler. 2005;11:306-309; J Am Pharm Assoc. 2005;45:371-375; Arch Neurol. 1997;54:531-533

*Neurology Reviews. 2012;20(2):5..

Establish Realistic Expectations

• DMTs decrease relapses, reduce MRI activity, and attenuate disease activity

• Attenuated disease activity may lead to more patients retaining employment

• Patients with MS must also realize that DMTs

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• Only work if patients take them• Do not “cure” MS• May not eliminate MS symptoms• Do not completely eliminate future disease activity

Abstract P05.073: 60th AAN 2008; Abstract P05.076: AAN 2008.

Benefits of Adherence to DMTs

• Relapse free at 1 year: 51%–80%• Relative decrease in ARR: 30%–80%• Absolute ARR: 0.15–0.7• Relative decrease in sustained progression:

31%–42%

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3 % %• Absolute rate of disease progression: 9%–18%• What this means?

– Untreated MS patient: relapse about every 6 months– Treated MS patient: relapse about every 2 to 5 years

Case Study (Part V)

• January 2011• TG has been receiving IFNβ-1b SQ since diagnosis

of MS• No new lesions on MRI• No new problems

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p• CC: Minor flu-like symptoms from IFNβ-1b SQ • At routine neurologist visit, TG asks about switching

to an alternative DMT (GA, natalizumab, or fingolimod)

Natalizumab

• Dosing: 300 mg IV every 4 weeks • Infusion reactions (e.g., rash, drowsiness, fever,

chills, nausea, flushing, decreased blood pressure, shortness of breath, chest pain) are common

– Usually occur within 2 hours of the start of the infusion

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– Generally subside when the drug is stopped and/or treatment with is given with diphenhydramine and/or steriods

Product information for Tysabri.


Natalizumab (Pivotal Trials)

• AFFIRM: – At 2-years, natalizumab decreased clinical relapses rates

by 66% and decreased ARR, compared to placebo

5151AFFIRM=Natalizmab safety and efficacy in relapsing remitting multiple sclerosis;

N Engl J Med. 2006;354:899-910.

Natalizumab (Pivotal Trials)

• SENTINEL: – IFN β-1a IM treated patients who continued to

experience disease activity were randomized to receive IFN β-1a IM monotherapy or IFN β-1a IM + natalizumab

– At 1-year the addition of natalizumab to IFN β-1a IM

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y βresulted in a 51% reduction in the rate of clinical relapses over IFN β-1a IM monotherapy; ARR also favored patients who received IFN β-1a IM + natalizumab

SENTINEL=Evaluating Addition of Tysabri to Avonex; N Engl J Med 2006;354:911-923.

Natalizumab (Safety)• Progressive multifocal leukoencephalopathy (PML)

– 150 cases confirmed as of September 30, 2011, 29 fatalApproximately 92,000 patients have received at least one dose of natalizumabRisk increases with exposure, particularly >24 months of therapyTesting for JC-virus?

• Hypersensitivity reactions – use diphenhydramine and methyprednisolone

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and methyprednisolone • NAbs• Melanomas/other cancers• Liver injury• Reactivation of latent viruses• Immune reconstitution inflammatory syndrome

(IRIS)

NAbs=neutralizing antibodies; Tysabri Product information.

1. Spain et al. BMC Medicine. 2009;7:74;

2. FDA drug safety communication: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders

/ucm199872.htm. Updated: February 5, 2010. Accessed: Janurary 25, 2012

TOUCH Prescribing Program

• Natalizumab should only be used as monotherapy• Natalizumab should only be used in patients who

have not responded adequately to, or who cannot tolerate, first-line DMTs

• Natalizumab can only be administered to patients

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Natalizumab can only be administered to patients enrolled in TOUCH

• Prior to initiating therapy, patients must receive MRI scans

• Patients must be evaluated 3 and 6 months after the first infusion and every 6 months thereafter

www.fda.gov/cder/drug/infopage/natalizumab/riskmap.pdf.

Fingolimod

• Dosing: 0.5 mg orally once daily• Pregnancy Category: C• Drug Interactions:

– Class Ia or III antiarrhythmic drugs– Ketoconazole

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– Live virus vaccines – Antineoplastic, immunosuppressive, or immunomodulating

therapies– Drugs that lower heart rate (eg, beta blockers, diltiazem)

Gilenya Product information.

Fingolimod (Safety)

• First-dose Effects– Bradycardia– Second degree Wenckebach atrioventricular block

• Lymphopenia– Reversal of lymphopenia can take weeks after the end of

d i d di th d

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dosing, depending on the dose

• Opportunistic infections• Malignancies

Ann Pharmacother. 2007;41:1660-1668;

N Engl J Med. 2006;355:1124-1140; WCTRIMS 2008. Abstract P72.


Fingolimod

• 11 Deaths reported as of January 20, 2012• 1 in the US

– Patient on at least a beta blocker and calcium channel blocker

• 10 in Europe

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– 6 unexplained deaths– 3 heart attacks– 1 EKG change

• Updated monitoring to include at least:– Do not use Fingolimod in any patient on a beta blocker or

calcium channel blocker– Increase monitoring to include telemetry on all patients

monitored with the first dose

Fingolimod (Pivotal Trials)

• FREEDOMS study– Examined the safety and efficacy of fingolimod in 1272

patients with RRMS– Patients received either placebo or fingolimod 0.5 mg or

1.25 mg once-daily– After 2 years the patients who received fingolimod (either

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After 2 years, the patients who received fingolimod (either dose) had reduced ARR compared to the patients who received placebo

FREEDOMS=FTY720 Research Evaluating Effects of Daily Oral therapy in Muliple Sclerosis; NEJM 2010, epub ahead of print.

Fingolimod (Pivotal Trials)

• TRANSFORMS study– Examined the safety and efficacy of fingolimod in 1292

patients with RRMS– Patients were randomized to receive oral fingolimod (0.5

mg or 1.25 mg) once-daily or IFNβ-1a IM 30 mcg IM once per week

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p– At 12 months, patients who received fingolimod (either

dose) had decreased ARR and MRI lesion activity, compared to the patients who received IFNβ-1a IM 30 mcg IM once per week

TRANSFORMS=TRial Assessing injectable interferoN (Avonex) vS FTY720 Oral in relapsing–Remitting Multiple Sclerosis; NEJM 2010, epub ahead of print.

Case Study (Part VI)

• March 2011• TG currently receiving IFNβ-1b SQ• No new lesions on MRI• No new problems• CC: Minor flu-like symptoms from IFNβ-1b SQ

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CC: Minor flu-like symptoms from IFNβ-1b SQ• At routine neurologist visit, TG inquires about the

treatments of MS that are under development.

Emerging Oral Therapies for MS

• Dimethyl fumarate (BG0012)• Laquinimod• Teriflunomide

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Dimethyl fumarate

• Being studied as an oral agent in MS• Proposed MOA:

– Induces “good” T-cells to kill “bad” T-cells, leading to a reduced migration of lymphocytes into the CNS

– Inflammatory and neuroprotective properties

6262Poster P50: Presented at WCTRIMS (Montreal, Quebec). 2008.


Dimethyl Fumarate (Pivotal Trial)

Study design: A total of 257 patients in this Phase II study received either 120 mg daily (low-dose), 120 mg three times daily (medium-dose), or 240 mg three times daily (high-dose)

Primary outcome: Comparison of the total number of new, active brain lesions at 4-week intervals starting at week 12

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active brain lesions at 4 week intervals starting at week 12

Findings:Compared with those on placebo, the high-dose treatment group had a 69% reduction in the mean total number of new enhancing MRI lesions from weeks 12 to 24The drug also reduced the number of other types of new or enlarging MRI lesions

Lancet. 2008;372:1463-1472.

Dimethyl fumarate (Safety)

• Gastrointestinal problems and flushing are the most commonly reported AEs

– Dissipate after ~6 weeks of treatment

6464CNS Drugs. 2007; 21:483-502.

Laquinimod

• An orally-administered, once-daily DMT being studied in MS

• Proposed MOA:

Appears to decrease inflammation in the CNS by increasing “good” T-cells (Th2) and by decreasing

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increasing good T-cells (Th2) and by decreasing “bad” T-cells (Th1)

Appears to reduce leukocyte infiltration into the CNS, which decreases demyelination and axonal damage

Journal of Neuroimaging. 2004;156:3-9.

Laquinimod (Pivotal Trial)

Study design: A total of 306 patients in this Phase Iib study received either placebo, low-dose laquinimod (0.3mg/day), or high-dose laquinimod (0.6mg/day)

Primary outcome: Cumulative number of Gd+ at weeks 24, 28, 32, and 36

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and 36

Findings:When compared with placebo, a statistically significant 40.4% reduction was found in the mean cumulative number of Gd+ lesions on the last four scans with the 0.6 mg dose The difference between results with the 0.3 mg dose and placebo was not statistically significant

Gd+=Gadolinium-enhancing; Lancet. 2008;371:2085-2092.

Laquinimod (Safety)

• No serious AEs emerged in clinical trials– Structurally related to roquinimex, a product shown to be

efficacious in MS in previous studies• Development of roquinimex was abandoned when it

was discovered that it caused MIs and systemic inflammatory syndromes

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y y• While laquinimod does not appear to be associated

with these AEs, continued vigilance is needed, because serious AEs are commonly not evident until Phase III studies or during post-marketing surveillance

Lancet. 2008;371:2085-2092.

Case Study (Part VII)

• March 2012• TG stopped IFNβ-1b SQ in April 2011• Five lesions on MRI• CC: Many symptomatic problems (ie, bladder

dysfunction, cognitive problems, depression, and

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y , g p , p ,fatigue)

• What needs to be done?


Approach to Treatment of Secondary MS Complications

• Treatment of acute exacerbations

• Modification of disease progression

• Managing symptomatic complications

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Managing symptomatic complications

Common Issues Facing Patients with Multiple Sclerosis

• Decreased cognition• Depression• Bladder dysfunction• Neuropathic pain• Spasticity• Walking/mobility issues

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Walking/mobility issues• Fatigue• Sexual dysfunction

All drugs in this section are off label for MS.All issues may be less severe or averted if patients are adherent to DMTs!!

Cognition

• ~50% of patients develop cognitive dysfunction, affecting their ability to think, reason, concentrate, or remember

• 5%–10% of patients suffer from moderate to severe cognitive impairment

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• Treatments include behavioral coping strategies, sometimes in combination with cholinesterase inhibitors (eg, donepezil) or stimulants

– Donepezil may have modest effects on verbal learning (ability to recall a list of words), memory, and attention

Neurol Clin. 2011; 29: 449-463; National Multiple Sclerosis Society. www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-

ms/symptoms/cognitive-function/index.aspx.O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and

Wilkins; 2006:227-255.

Cholinesterase Inhibitors & Noncompetitive NMDA Receptor Antagonist

• Donepezil (Aricept)• Rivastigmine (Exelon)• Galantamine (Razadyne/Razadyne ER)• Memantine (Namenda)

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Memantine (Namenda)

• REMEMBER to remove anticholinergics if cognitive dysfunction starts after their initiation!

Stimulants or Activating Drugs

• Amantadine (Symmetrel) • Methylphenidate (Ritalin)• Dextroamphetamine (Dexedrine)• Modafinil (Provigil)• Fluoxetine (Prozac)

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Fluoxetine (Prozac)• Dalfampridine (Ampyra)

Cognition

• Since cognitive impairment can negatively impact patient adherence, pharmacists should make all attempts to simplify drug regimens

– Suggest medications that can be given once per day rather than multiple times per dayRecommend monotherapy options instead of

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– Recommend monotherapy options instead of multidrug ones

– Attempt to use drugs for >1 use


Depression

• ~ 50% of all MS patients suffer from depression• The exact cause of MS-related depression is not

known– Psychological reaction to a chronic illness– Part of the grieving process (3–6 months)

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– Related to the neuropathology of MS– Interferons may precipitate or worsen

• Relationship between fatigue/depression– Fatigue Depression– Depression Fatigue

Neurol Clin. 2011; 29: 449-463; O’Conner P. In: Multiple Sclerosis and DemyelinatingDiseases. Lippincott, Williams, and Wilkins; 2006:227-255.

Treating DepressionPharmacologic Treatments

• Treatment similar to major depressive disorder • Selective serotonin reuptake inhibitors (SSRIs),

serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, tricyclic antidepressants (TCAs), mirtazapine

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• Consider comorbidities when selecting agent

O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255.

Treating DepressionComorbid Conditions

• Insomnia Mirtazapine, TCAs• Neuropathy Duloxetine, TCAs• Sexual dysfunction Bupropion• Fatigue SNRIs (venlafaxine, duloxetine,

desvenlafaxine), fluoxetine, stimulants

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des e a a e), uo e e, s u a s• Cognition/balance Avoid TCAs• Incontinence SNRIs, TCAs


Treating DepressionPatient Counseling Tips

• Bupropion, fluoxetine, and SNRIs considered activating

– May initially provide benefit for fatigue

• Sertraline, citalopram, escitalopram – Neutral

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• Paroxetine considered sedating– Initially may benefit sleep

• TCAs typically cause drowsiness– May worsen symptoms of neurogenic bladder due

to excessive urinary retention– Be aware of anticholinergic side effects at higher doses

(salivation, lacrimation, urination, defecation)


Treating DepressionPatient Counseling Tips

• Benefits take 6–8 weeks• Treatment duration varies• Treatment failure anticipated• Suicide is 7 times more common than

in the general population

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g p p• Start low, go slow

– Limiting side effects– Escalate to maximum tolerated dose

• Tricyclic antidepressants more lethal in overdose

Bladder Dysfunction• Bladder dysfunction problems include failure to empty, failure

to store, nocturia or a combination1,2

• Nocturia• Failure to empty (hyporeflexive bladder)• Failure to store (hyperreflexive bladder)

– The most common bladder problem seen in MS patients1,2

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– Manifests as urinary urgency and frequency and voiding only small amounts of urine1,2

– Over time, urgency can become more difficult to control and can lead to incontinence2

– Failure to store/incomplete bladder emptying (sphincter detrusor dyssynergia)

• May occur more frequently in men• Causes hesitancy, retention, and overflow incontinence

1. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255. 2. Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.


Bladder DysfunctionNonpharmacologic and Prophylactic Treatments

• Hyporeflexive bladder (failure to empty)– Crede maneuver, timed voids, catheterization

• Long-term complications – Urinary tract infections (UTIs)– Urosepsis

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p

• UTI prophylaxis– Sulfamethoxazole/trimethoprim sulfate– Cephalexin– Nitrofurantoin– Cinoxacin

Schapiro RT, et al. In: Multiple Sclerosis: Clinical and Pathogenetic Basis. Lippincott Williams & Wilkins;1997:391-420. Schapiro RT. Neurorehabil Neural Repair. 2002;16:223-

231. Bainbridge JL, et al. In: Pharmacotherapy: A Pathophysiological Approach. 7th edition. New York, New York: McGraw-Hill; 2008:913-926.

Bladder DysfunctionPharmacologic Treatments

• Failure to empty (hyporeflexive bladder)– Cholinergic agents (bethanechol chloride)

• Nocturia– Desmopressin acetate (DDAVP)

8282Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.

Bladder DysfunctionPharmacologic Treatments

• Failure to store (hyperreflexive bladder)– Anticholinergic medications (eg, oxybutynin, tolterodine)1,2

– With or without low-dose imipramine (synergistic effect)

– Remove cholinergic agent if incontinence started soon after its initiation

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after its initiation

• Failure to store (sphincter dyssynergia)– Alpha blocking drugs (eg, terazosin and tamsulosin,

alfuzosin, silodosin) are the drugs of choice for failure to store problems1,2

– Relaxes the internal sphincter

1. Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.2. Schapiro RT. Neurorehabil Neural Repair. 2002;16:223-231.

Treatment—Urge UI/OAB(Based on Cost/Insurance Coverage)

1st Line• Oxybutynin:

2.5–5 mg 2–4 times daily• Oxybutynin XL (Ditropan

XL): 5–30 mg daily• Oxybutynin gel (Gelnique):

2nd Line• Oxybutynin patch (Oxytrol):

3.9 mg 2x/week• Fesoterodine (Toviaz):

4–8 mg ER daily• Trospium (Sanctura):

20 mg 1 2 times daily not

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Oxybutynin gel (Gelnique): 1 g daily

• Tolterodine (Detrol): 1–2 mg twice daily – w/3A4 inhibitor, decrease dose

• Tolterodine LA (Detrol LA): 2–4 mg daily

20 mg 1–2 times daily – not metabolized

• Trospium XR (Sanctura XR): 60 mg daily

• Solifenacin (Vesicare): 5–10 mg daily

• Darifenacin (Enablex): 7.5–15 mg daily

Abbreviations: OAB, overactive bladder; UI, urinary incontinence.

Comparison of OAB Agents

Drug Dry Mouth(%)

Constipation(%)

Dizziness(%)

VisionChanges

(%)Oxybutynin 85 40 32 20Oxy ER/XL 35 7 5 2Oxy TDS 7 3 1 1

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Oxy gel 8 1 3 ?Tolterodine 61, 23 13, 6 6, 2 8, 1

Fesoterodine 35 6 ? ?Trospium 20 10 1 1Solifenacin 11 5 2 4Darifenacin 20 15 2 2

Differentiation of Muscarinic Receptors in the CNS

• M1: antagonists impair memory and cognition• M2: antagonists enhance cognition• M3: antagonists cause no deficit in memory or

cognition• M4: antagonists may enhance acetylcholine in the

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g y ybrain; no effect on cognition

• M5: antagonists cause no deficit in memory or cognition

Wess J. Annu Rev Pharmacol Toxicol. 2004;44:423-450.


Bladder DysfunctionPatient Counseling Tips

• Anticholinergic medications– Most common adverse effects (AEs)—dry mouth

and constipation– AEs more common with immediate-release

formulations– Remind patients to increase fluid intake

Adh i t t ith t i d l

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– Adherence very important with sustained-release formulations

• Alpha-blocking agents– These products decrease blood pressure and can

cause severe dizziness, especially after the 1st dose


Sensory and Pain Symptoms

• Sensory symptoms– Trigeminal neuralgia (one of the more common

symptoms)– Burning, itching, L’Hermitte’s sign, face twitching – Carbamazepine 200 mg PO BID or TID

Gabapentin topiramate tiagabine tricyclic

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– Gabapentin, topiramate, tiagabine, tricyclic antidepressants (TCAs)

• Neuropathic pain (50%)– Difficult to treat– Carbamazepine, TCAs, gabapentin, pregabalin,

duloxetine, topiramate, tiagabine, capsaicin cream, etc

Schapiro RT. Neurorehabil Neural Repair. 2002;16:223-231. Schapiro RT. Ann Indian Acad Neurol. 2009;12:291-295.

Henze T, et al. Eur Neurol. 2006;56:78-105.

Spasticity

• Affects up to 70% of patients with MS• Leading cause of disability in MS• A velocity-dependent increase in muscle tone,

derived from hyperexcitability of the stretch reflex– Primarily affects the lower limbs and can lead to pain,

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stiffness, tremor, clonus, impaired balance, and spasms


Spasticity

• Clinical manifestations include – Phasic spasticity (spasms, cramps, and clonus)1

– Tonic spasticity (stiffness)1

• Can be induced by a variety of noxious stimuli (eg, urinary tract infections, constipation, pressure l l fi i i i li i d i )2 3

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ulcers, poorly fitting assistive living devices)2,3

• IFN-β products enhance nerve conduction in the spinal cord and can exacerbate spasticity2

1. Henze T. Int MS J. 2007;14:22-27. 2. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams,

and Wilkins; 2006:227-255. 3. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

Spasticity

• The goal of therapy is to reduce symptoms in order to improve patient comfort and function, rather than to completely eliminate the spasticity

• Some degree of spasticity actually helps patients with lower-extremity weakness walk because it ff li b bili i

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offers some limb stabilization


SpasticityNonpharmacologic Treatments

• Nonpharmacologic treatments should be used prior to pharmacologic treatments

• Physical therapy– Exercises (stretching and range of motion)

• Aquatic exercises are popular; critical that water t t b i t l 85 F (

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temperature be approximately 85oF (warmer temperatures cause fatigue; colder temperatures exacerbate spasticity)

• Mechanical aids– Orthotics– Braces


Henze T. Int MS J. 2007;14:22-27. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.


SpasticityPharmacologic Treatments

• Always start out with the lowest possible dose and slowly escalate doses upward as needed

• Oral baclofen is the drug of choice– Adverse events (AEs) include somnolence

d f i

9393

and confusion– AEs decrease over time– Avoid suddenly stopping the drug


Spasticity Pharmacologic Treatments

• Second-line agents; frequently used in combination with oral baclofen

– Tizanidine– Diazepam– Clonazepam

D t l

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– Dantrolene– Clonidine

• Refractory spasticity– Botulinum toxin– Intrathecal baclofen


Henze T. Int MS J. 2007;14:22-27. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

SpasticityPatient Counseling Tips

• It is common for patients to be on >1 antispasticity medication at the same time

• All of the oral agents cause drowsiness– Can worsen fatigue/cognition

• When initiating therapy with oral antispasticity

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agents, start in the evening (at bedtime)• Very dangerous for patients to go “cold turkey” with

baclofen (oral or intrathecal)– Seizures, hallucinations, and death can result– Refill reminders from pharmacist!


Walking/Mobility Issues

• Gait disturbances are a common symptomatic problem

• Extended Disability Status Scale (EDSS) scoring used to assess walking mobility issues

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EDSS Scoring

9797Available at: www.msdecisions.org.uk.

Kurtzke JF, et al. Neurology. 1983;33:1442-1452.


• Traditionally have been managed using nonpharmacologic treatments (ie, exercise, physical therapy, gait training, assistive devices)

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• Dalfampridine was recently approved by the FDA: 1st approved treatment for improved walking in patients with MS

• Exactly how dalfampridine improves walking is not known

9999

– It has been proposed that dalfampridine improves conduction in nerve fibers in which myelin has been damaged, thus improving mobility

Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.

Dalfampridine Pivotal Trials

• Evaluated in 2 controlled trials involving 540 patients

– Study 1: randomized, placebo-controlled, parallel group, 21-week study in 301 patients1

– Study 2: randomized, placebo-controlled, parallel group, 14-week study in 239 patients2

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14 week study in 239 patients2

• Primary efficacy measure in both studies was walking speed as measured by the Timed 25-foot Walk

1. Goodman AD, et al. Lancet. 2009;373:732-738. 2. Goodman AD, et al. Mult Scler. 2008;14:S298. Abstr. P909.

Dalfampridine Pivotal Trials

• In both studies, dalfampridine-treated patients had significantly improved walking speeds

– Trial 1: 34.8% vs 8.3% (P <.0001)1

– Trial 2: 42.9% vs 9.3% (P <.001)2

A i ifi l i f i ki

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• A significantly greater proportion of patients taking dalfampridine had increased walking speed of at least 10%, 20%, or 30% from baseline, vs placebo3

1. Goodman AD, et al. Lancet. 2009;373:732-738. 2. Goodman AD, et al. Mult Scler. 2008;14:S298. Abstr. P909.

3. Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.

DalfampridinePatient Counseling Tips

• The first dose should be taken first thing in the morning, and the second dose should be taken approximately 12 hours later

• Tell patients to take missed doses as soon as possible unless it is almost time for the next dose (k i 12 h b d

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(keeping 12 hours between doses to prevent adverse events)


DalfampridinePatient Counseling Tips

• Can be taken with or without food • Tablets should be swallowed whole; they should

never be broken, crushed, or chewed • Patients who have a history of seizures or moderate

to severe renal impairment, or who are already

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taking compounded 4-aminopyridine, should not take dalfampridine


Dalfampridinevs 4-Aminopyridine

• Not bioequivalent• Cannot be substituted• Dalfampridine only indicated for walking/mobility

issues

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Fatigue

• 60%–97% of patients report fatigue1,2,3

• 15%–40% report that it is the worst symptom of their disease1

• Traditionally, fatigue has been evaluated through patient self-reporting questionnaires

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– Subjective – Can be confounded by other symptoms

1. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255. 2. Goldman MD, et al.

Cleve Clin J Med. 2006;73:177-186. 3. Henze T. Int MS J. 2007;14:22-27.

Fatigue

• Proper evaluation and treatment should take into account physical conditioning; management of pain, sleep, or mood disorders; laboratory studies to rule out other potential causes of fatigue

• Rule out other factors that may cause fatigue

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– Adverse events– Depression– Sleep disorders– Other metabolic conditions or diseases– Interferon β products

Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186. Henze T. Int MS J. 2007;14:22-27.

Treating FatigueNonpharmacologic Treatments

• Management requires a multidisciplinary approach ⎯ physical therapy, psychology, neurology, and psychiatry

– Fatigue resulting from extreme spasticity may be lessened by stretching exercises and/or antispasm medicationsFatigue resulting from an infection requires treatment of

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– Fatigue resulting from an infection requires treatment of the underlying condition

– Fatigue arising from a mood disorder may respond best to combination therapy with medications and counseling

– Fatigue arising from lifestyle factors (ie, overexertion) may respond to teaching patients to not overexert themselves


Treating FatiguePharmacologic Treatments

• Modafinil1-3

– 100–400 mg once daily in the AM– First-line agent for improving daytime fatigue

• 4-aminopyridine1-3

– 5–20 mg twice daily (AM and in the early afternoon)

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– Especially effective in treating heat-related fatigue

• Selective serotonin reuptake inhibitors (ie, fluoxetine)1,2

– 10–40 mg once daily in the AM– Improves daytime fatigue associated with depression

• Amantadine1-3

– 100 mg twice daily (AM and in the early afternoon)1. Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.

2. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255. 3. Henze T. Int MS J. 2007;14:22-27.

Treating FatiguePatient Counseling Tips

• Many of the medications used to treat other symptomatic problems can cause drowsiness and worsen the symptoms of fatigue

– When possible, such medications should be taken around naptime or at bedtime

• Modafinil can reduce the efficacy of hormonal

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• Modafinil can reduce the efficacy of hormonal contraception1

– Remind women of childbearing age who use oral contraceptives to use back-up contraception

1. Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.

Sexual Dysfunction

• Common in both males and females1-3

• Affects ~75% of patients1,3

• Can be caused by a variety of factors2,3

– Depression– Fatigue

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– Neurologic impairment– Pain– Concurrent medications

1. Henze T. Int MS J. 2007;14:22-27. 2. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255.

3. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.


Pharmacologic and Other Agents That Cause Sexual Dysfunction

• Alcohol• Beta blockers• Certain antidepressants, including fluoxetine,

paroxetine, and sertraline• Monoamine oxidase inhibitors

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o oa e o dase b o s• Tricyclic antidepressants

1. Henze T. Int MS J. 2007;14:22-27. 2. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255.

3. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

Treating Sexual Dysfunction in Males

• First line– Phosphodiesterase inhibitors (eg, sildenafil)1-4

• Second line– Alprostadil injections– Amantadine

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– Penile prosthetic devices1,2

1. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255. 2. Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.

3. Henze T. Int MS J. 2007;14:22-27. 4. Crayton H, et al. Neurology. 2004;63(11 suppl 5):S12-18.

Treating Sexual Dysfunction in Females

• Not easily treated with pharmacologic agents • Sildenafil studies not effective in women• Lack of lubrication can also cause

female-related sexual problems

113113O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases.

Lippincott, Williams, and Wilkins; 2006:227-255.

First-line therapies

Consistent effect on relapses and MRIUnclear effect on long-term disability

Potential to further enhance efficacy and ease of use

GAIFNβ

FingolimodNatalizumab

Tx-naive patients

Emerging MS Therapies

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Oral agents Laquinimod

TeriflunomideFumaric acid (BG-12)

Monoclonal antibodiesDaclizumab

AlemtuzumabRituximab

Ocrelizumab

Combination therapyIFNβ-basedGA-based

Novel agents

Main emerging therapies and strategies

MS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at: http://www.msforum.net/Site/Slide-Sets-And-CD-Roms/

Summary

• MS symptomatic problems significantly impact patients functioning and quality of life

• Although total elimination of symptoms may not be possible, most can be treated with a variety of nonpharmacologic and pharmacologic strategies

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• Effective management of MS-related symptoms requires a coordinated, multidisciplinary approach that includes pharmacists, physical therapists, psychologists, and neurologists

• Health care practitioners should stress to patients the importance of adhering to all treatment regimens in order to reduce MS-related symptoms and improve their quality of life

Which Drug Used to Treat Multiple Sclerosis Requires a First Dose Observation Period?

0%

0% 1.Dalfampridine2.Glatiramer acetate3

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0%

0% 3.Fingolimod4. Interferon Beta 1a


EG Reports Severe Flu-Like Symptoms with her Multiple Sclerosis Therapy. Which First Line Drug Would be your Next Choice?

0%

0% 1.Fingolimod2.Glatiramer acetate3

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0%

0% 3. Interferon Beta 1b4. Interferon Gamma 1a

MB is Experiencing Fatigue and Depression. Which Drug is a Good Option for this Patient?

0%

0% 1.Amitriptyline2.Mirtazapine3

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0%

0% 3. Imipramine4.Fluoxetine

RP is Complaining of Problems Walking. You Recommend Which of the Following Drugs at add to his Multiple Sclerosis Therapy?

0%

0% 1.Dalfampridine2.Bupropion3

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0%

0% 3.Modafinil4.Natalizumab

Which Option Below has Proven to Promote Adherence in Multiple Sclerosis Patients

0%

0%

0% 1. Set realistic expectations2. Nonadherence is not a problem3 Give a drug holiday

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0%

0% 3. Give a drug holiday4. Defer the drug copay

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