Multiple Sclerosis

2012 by the American Pharmacists Association. All rights reserved.
Multiple Sclerosis:
Managing the Whole Patient
Jacquelyn Bainbridge, PharmD, FCCP
Professor, Department of Clinical Pharmacy and Neurology,
University of Colorado
Ellen Whipple Guthrie, PharmD
Medical Advisory Board, MS Foundation
Clinical Assistant Professor, University of Georgia College of
Pharmacy
Supported by independent
educational grants from
22
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
44
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
55
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. Dalfampridine
2. Glatiramer acetate
3
66
0%
0% 3. Fingolimod
4. 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. Fingolimod
3
77
0%
0% 3. Interferon Beta 1b
4. Interferon Gamma 1a
MB is Experiencing Fatigue and
Depression. Which Drug is a
Good Option for this Patient?
0%
0%
1. Amitriptyline
2. Mirtazapine
3
88
0%
0% 3. Imipramine
4. Fluoxetine
RP is Complaining of Problems
Walking. You Recommend Which
of the Following Drugs at add to
his Multiple Sclerosis Therapy?
0%
0%
1. Dalfampridine
2. Bupropion
3
99
0%
0% 3. Modafinil
4. Natalizumab
Which Option Below has Proven
to Promote Adherence in Multiple
Sclerosis Patients
0%
0%
0% 1. Set realistic expectations
2. Nonadherence is not a problem
3 Give a drug holiday
10 10
0%
0%
3. Give a drug holiday
4. 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
11 11
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:
12 12
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
13 13
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
14 14
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:
15 15
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
16 16
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)
*
17 17
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
IFN IFN induced proteins
b2-Microglobulin, Neopterin, TRAIL, myoxvirus resistance
protein A (MxA)
Binding antibodies (BAb) + IFN IFN induced
proteins
18 18
Neutralizing antibodies (NAb) + IFN IFN
induced proteins, therefore; decreased clinical
effect of IFN*
In Scandinavian countries discontinuation of IFN
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 definiteMS (CDMS)
19 19
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)
ProgressinNeurobiology. 2011;95:670-685.
Approach to
Multiple Sclerosis Therapy
Treatment of acute exacerbations
Modification of disease progression
Managing symptomatic complications
21 21
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
22 22
CC Cu e y gs a e b u y e g eye
Normal findings on MRI
Patients 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
23 23
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?
24 24
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
25 25
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
26 26
) 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 T
2
lesion in a
least 2 out of 4 areas of the brain
CDMS=clinicallydefinedmultiplesclerosis; CSF=cerebrospinal fluid; MAGNIMS =EuropeanMulticent
CollaborativeResearchNetwork onMRI inMS
Neurol. 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.
27 27
CIS=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
28 28
CDMS, through the use of early therapeutic
intervention.
Prognosis in CIS
Rate of Conversion to CDMS
80
100
0 Lesions
o

C
D
M
S
Baseline Measure
29 29
0
20
40
60
5 10 15
0 Lesions
13 Lesions
410 Lesions
>10 Lesions
Years
%

C
o
n
v
e
r
t
i
n
g

t
o
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
GA
1
CIS, RRMS 20 mg SQ once daily
30 30
IFN-1a IM
2
CIS, RRMS 30 mcg IM 1x/week
IFN-1a SQ
3
RRMS* 22-44 mcg SQ 3x/week
IFN-1b
4,5
CIS, RRMS 250 mcg SQ every-other day
*FDAexpected 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;
1
Product information for Copaxone;
2
Product information for Avonex;
3
Product information for Rebif;
4
Product information for Extavia;
5
Product information for Betaseron.
Efficacy in CIS
Clinical Studies
Name Agents/Dosing Findings (vs. placebo)
PreCISe
Trial
1
GA 20 mg/day vs.
placebo
At 3 years, GA ed the
conversion to CDMS by 45%.
BENEFIT
Trial
2
IFN -1b 250 mcg
every-other day vs.
l b
At 2 years, IFN -1b ed the
31 31
placebo
y
CHAMPS
Trial
3
IFN -1a 30 mcg
1x/week vs. placebo
At 3 years, IFN -1a ed the
REFLEX
Trial
4
IFN -1a 44 mcg
3x/week vs. placebo
At 2 years, IFN -1a ed the
BENEFIT=Betaferon in newly emerging MS for initial treatment
CHAMPS=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.
1
Lancet.2009;66:841-6;
2
Neurology. 2006;67:1242-49;
3
N
Engl J Med.2000;343:898-904.
5
Merck-Serono Press Release, October 2010.
Case Study (Part II-cont)
Patient decides to not start treatment with a DMT
because of needle phobia
32 32
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
33 33
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.
34 34
IFN Products
3 formulations (IFN -1b SQ, IFN -1a IM, and
IFN -1a SQ)
Pregnancy Category: C
Drug Interactions: Possibly hepatically active
drugs
35 35
drugs
Laboratory monitoring: CBC, LFT, TSH
Product information for Avonex, Betaseron, Extavia, and Rebif.
IFN- (Formulations)
IFN -1a IM
Low dose IFN- product
30 mcg IM every week
IFN -1b SQ
High dose IFN- product
36 36
High dose IFN product
250 mcg SQ every other day
IFN -1a SQ
High dose IFN- product
(22 mcg low dose) to 44 mcg SQ every other day
Product information for Avonex, Betaseron, Extavia, and Rebif.
IFN- (MOA)
Does not cross the BBB
Works outside of the CNS to reduce inflammation
Stabilizes the BBB
Decreases matrix metalloproteinases
No evidence of neuroprotection
37 37
o e de ce o eu op o ec o
BBB=blood brain barrier; Product information for Avonex, Betaseron, Extavia, and Rebif.
IFN- (Safety)
Menstrual irregularities
Flu-like symptoms
Injection site reactions
Depression
38 38 Product information for Avonex, Betaseron, Extavia, and Rebif.
IFN- (Pivotal Trials)
IFN -1b
SQ
Decreased frequency of relapses; more
patients free of relapses over a 2-year
treatment period
1
IFN -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
39 39
fewer patients developed CDMS over a 3-
year follow-up period
2
IFN -1a
SQ
PRISMS
3
/3EVIDENCE
4
: 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;
1
Neurology. 1993;43:655-661;
2
N Engl J Med. 2000;343(13):898-
904;
3
Lancet. 1998;352:1498-1504;
4
Lancet .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
40 40 Product information for Copaxone.
GA (MOA)
Not an IFN- product
Produces T-cells that suppress the immune attack
on myelin
Resembles myelin basic protein
Exerts effect within the BBB
41 41
Exerts effect within the BBB
Neuroprotective properties
Product information for Copaxone.
GA (Safety)
Injection site reactions
Hives
Post injection reaction
42 42 Product 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 placebo
1
After 15-years, patients who remained in the study
43 43
and received GA experienced stabilized or
improved EDSS, and 65% had not yet transitioned
to SPMS
2
ARR=annualized release rate; RRMS=relapsing-remitting multiple sclerosis;
EDSS=Expanded Disability Status Scale; SPMS=secondary-progressive multiple
sclerosis;
1
Neurology 1995; 45:1268-1276;
2
Press release, The Consortium of
Multiple Sclerosis Centers, February 2010.
Case Study (Part IV-cont)
October 2010
Patient and MD decide on IFN -1b SQ 250 mcg
every other day
Pharmacy consult
Injection training
44 44
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
45 45
ce e a ea be o e a d a e jec g e
medication
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
46 46
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
47 47
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: 0.150.7
Relative decrease in sustained progression:
31%42%
48 48
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 IFN-1b SQ since diagnosis
of MS
No new lesions on MRI
No new problems
49 49
p
CC: Minor flu-like symptoms from IFN-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
50 50
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
51 51
AFFIRM=Natalizmab safety and efficacy in relapsing remitting multiple sclerosis;
N Engl J Med. 2006;354:899-910.
Natalizumab (Pivotal Trials)
SENTINEL:
IFN -1a IM treated patients who continued to
experience disease activity were randomized to
receive IFN -1a IM monotherapy or IFN -1a IM +
natalizumab
At 1-year the addition of natalizumab to IFN -1a IM
52 52
y
resulted in a 51% reduction in the rate of clinical
relapses over IFN -1a IM monotherapy; ARR also
favored patients who received IFN -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 fatal
Approximately 92,000 patients have received at least one
dose of natalizumab
Risk increases with exposure, particularly >24 months of
therapy
Testing for JC-virus?
Hypersensitivity reactions use diphenhydramine
and methyprednisolone
53 53
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
54 54
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
55 55
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
56 56
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
57 57
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
58 58
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 IFN-1a IM 30 mcg IM once
per week
59 59
p
At 12 months, patients who received fingolimod (either
dose) had decreased ARR and MRI lesion activity,
compared to the patients who received IFN-1a IM 30
mcg IM once per week
TRANSFORMS=TRial Assessing injectable interferoN (Avonex) vS FTY720 Oral in
relapsingRemitting Multiple Sclerosis; NEJM 2010, epub ahead of print.
Case Study (Part VI)
March 2011
TG currently receiving IFN-1b SQ
No new lesions on MRI
No new problems
60 60
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
61 61
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
62 62 Poster 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
63 63
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 24
The 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
64 64 CNS 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
65 65
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
66 66
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
67 67
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 IFN-1b SQ in April 2011
Five lesions on MRI
CC: Many symptomatic problems (ie, bladder
dysfunction, cognitive problems, depression, and
68 68
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
69 69
Common Issues Facing Patients
with Multiple Sclerosis
Decreased cognition
Depression
Bladder dysfunction
Neuropathic pain
Spasticity
Walking/mobility issues
70 70
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
71 71
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.
OConner 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)
72 72
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)
73 73
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 day
Recommend monotherapy options instead of
74 74
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 (36 months)
75 75
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; OConner P. In: Multiple Sclerosis and Demyelinating
Diseases. Lippincott, Williams, and Wilkins; 2006:227-255.
Treating Depression
Pharmacologic Treatments
Treatment similar to major depressive disorder
Selective serotonin reuptake inhibitors (SSRIs),
serotonin norepinephrine reuptake inhibitors
(SNRIs), bupropion, tricyclic antidepressants
(TCAs), mirtazapine
76 76
Consider comorbidities when selecting agent
OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, andWilkins;
2006:227-255.
Treating Depression
Comorbid Conditions
Insomnia Mirtazapine, TCAs
Neuropathy Duloxetine, TCAs
Sexual dysfunction Bupropion
Fatigue SNRIs (venlafaxine, duloxetine,
desvenlafaxine), fluoxetine, stimulants
77 77
des e a a e), uo e e, s u a s
Cognition/balance Avoid TCAs
Incontinence SNRIs, TCAs
Wilkins; 2006:227-255.
Treating Depression
Patient Counseling Tips
Bupropion, fluoxetine, and SNRIs considered
activating
May initially provide benefit for fatigue
Sertraline, citalopram, escitalopram
Neutral
78 78
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)
Wilkins; 2006:227-255.
Treating Depression
Benefits take 68 weeks
Treatment duration varies
Treatment failure anticipated
Suicide is 7 times more common than
in the general population
79 79
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 combination
1,2
Nocturia
Failure to empty (hyporeflexive bladder)
Failure to store (hyperreflexive bladder)
The most common bladder problem seen in MS patients
1,2
80 80
Manifests as urinary urgency and frequency and voiding only
small amounts of urine
1,2
Over time, urgency can become more difficult to control and can
lead to incontinence
2
Failure to store/incomplete bladder emptying (sphincter detrusor
dyssynergia)
May occur more frequently in men
Causes hesitancy, retention, and overflow incontinence
1. OConner 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 Dysfunction
Nonpharmacologic and
Prophylactic Treatments
Hyporeflexive bladder (failure to empty)
Crede maneuver, timed voids, catheterization
Long-term complications
Urinary tract infections (UTIs)
Urosepsis
81 81
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 Dysfunction
Failure to empty (hyporeflexive bladder)
Cholinergic agents (bethanechol chloride)
Nocturia
Desmopressin acetate (DDAVP)
82 82 Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.
Bladder Dysfunction
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
83 83
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 problems
1,2
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.
TreatmentUrge UI/OAB
(Based on Cost/Insurance Coverage)
1st Line
Oxybutynin:
2.55 mg 24 times daily
Oxybutynin XL (Ditropan
XL): 530 mg daily
Oxybutynin gel (Gelnique):
2nd Line
Oxybutynin patch (Oxytrol):
3.9 mg 2x/week
Fesoterodine (Toviaz):
48 mg ER daily
Trospium (Sanctura):
20 mg 1 2 times daily not
84 84
Oxybutynin gel (Gelnique):
1 g daily
Tolterodine (Detrol):
12 mg twice daily w/3A4
inhibitor, decrease dose
Tolterodine LA (Detrol LA):
24 mg daily
20 mg 12 times daily not
metabolized
Trospium XR (Sanctura XR):
60 mg daily
Solifenacin (Vesicare):
510 mg daily
Darifenacin (Enablex):
7.515 mg daily
Abbreviations: OAB, overactive bladder; UI, urinary incontinence.
Comparison of OAB Agents
Drug
Dry Mouth
(%)
Constipation
(%)
Dizziness
(%)
Vision
Changes
(%)
Oxybutynin 85 40 32 20
Oxy ER/XL 35 7 5 2
Oxy TDS 7 3 1 1
85 85
Oxy gel 8 1 3 ?
Tolterodine 61, 23 13, 6 6, 2 8, 1
Fesoterodine 35 6 ? ?
Trospium 20 10 1 1
Solifenacin 11 5 2 4
Darifenacin 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
86 86
g y y
brain; no effect on cognition
M5: antagonists cause no deficit in memory or
cognition
Wess J. Annu Rev Pharmacol Toxicol. 2004;44:423-450.
Bladder Dysfunction
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
87 87
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
OConner P. In: Multiple Sclerosis and Demyelinating Diseases.
Lippincott, Williams, and Wilkins; 2006:227-255.
Sensory and Pain Symptoms
Sensory symptoms
Trigeminal neuralgia (one of the more common
symptoms)
Burning, itching, LHermittes sign, face twitching
Carbamazepine 200 mg PO BID or TID
Gabapentin topiramate tiagabine tricyclic
88 88
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,
89 89
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
90 90
ulcers, poorly fitting assistive living devices)
2,3
IFN- products enhance nerve conduction in the
spinal cord and can exacerbate spasticity
2
1. Henze T. Int MS J. 2007;14:22-27.
2. OConner 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
91 91
offers some limb stabilization
Spasticity
Nonpharmacologic 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 (
92 92
temperature be approximately 85oF (warmer
temperatures cause fatigue; colder temperatures
exacerbate spasticity)
Mechanical aids
Orthotics
Braces
OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams,
and Wilkins; 2006:227-255.
Henze T. Int MS J. 2007;14:22-27.
Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.
Spasticity
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
93 93
and confusion
AEs decrease over time
Avoid suddenly stopping the drug
Spasticity
Second-line agents; frequently used in combination
with oral baclofen
Tizanidine
Diazepam
Clonazepam
D t l
94 94
Dantrolene
Clonidine
Refractory spasticity
Botulinum toxin
Intrathecal baclofen
OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams,
and Wilkins; 2006:227-255.
Henze T. Int MS J. 2007;14:22-27.
Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.
Spasticity
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
95 95
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
96 96
EDSS Scoring
97 97
Available 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)
98 98
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
99 99
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
100 100
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
101 101
A significantly greater proportion of patients taking
dalfampridine had increased walking speed of at
least 10%, 20%, or 30% from baseline, vs placebo
3
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.
Dalfampridine
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
102 102
(keeping 12 hours between doses to prevent
adverse events)
Dalfampridine
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
103 103
taking compounded
4-aminopyridine, should not take dalfampridine
Dalfampridine
vs 4-Aminopyridine
Not bioequivalent
Cannot be substituted
Dalfampridine only indicated for walking/mobility
issues
104 104
Fatigue
60%97% of patients report fatigue
1,2,3
15%40% report that it is the worst symptom of
their disease
1
Traditionally, fatigue has been evaluated through
patient self-reporting questionnaires
105 105
Subjective
Can be confounded by other symptoms
1. OConner 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
106 106
Adverse events
Depression
Sleep disorders
Other metabolic conditions or diseases
Interferon products
Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.
Henze T. Int MS J. 2007;14:22-27.
Treating Fatigue
Nonpharmacologic 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 medications
Fatigue resulting from an infection requires treatment of
107 107
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 Fatigue
Modafinil
1-3
100400 mg once daily in the AM
First-line agent for improving daytime fatigue
4-aminopyridine
1-3
520 mg twice daily (AM and in the early afternoon)
108 108
Especially effective in treating heat-related fatigue
Selective serotonin reuptake inhibitors (ie,
fluoxetine)
1,2
1040 mg once daily in the AM
Improves daytime fatigue associated with depression
Amantadine
1-3
100 mg twice daily (AM and in the early afternoon)
and Wilkins; 2006:227-255. 3. Henze T. Int MS J. 2007;14:22-27.
Treating Fatigue
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
109 109
Modafinil can reduce the efficacy of hormonal
contraception1
Remind women of childbearing age who use oral
contraceptives to use back-up contraception
Sexual Dysfunction
Common in both males and females
1-3
Affects ~75% of patients
1,3
Can be caused by a variety of factors
2,3
Depression
Fatigue
110 110
Neurologic impairment
Pain
Concurrent medications
1. Henze T. Int MS J. 2007;14:22-27. 2. OConner P. In: Multiple Sclerosis and
Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255.
Pharmacologic and Other Agents
That Cause Sexual Dysfunction
Alcohol
Beta blockers
Certain antidepressants, including fluoxetine,
paroxetine, and sertraline
Monoamine oxidase inhibitors
111 111
o oa e o dase b o s
Tricyclic antidepressants
1. Henze T. Int MS J. 2007;14:22-27. 2. OConner P. In: Multiple Sclerosis and
Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227-255.
Treating Sexual Dysfunction
in Males
First line
Phosphodiesterase inhibitors (eg, sildenafil)
1-4
Second line
Alprostadil injections
Amantadine
112 112
Penile prosthetic devices
1,2
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
113 113
First-line therapies
Consistent effect on relapses and MRI
Unclear effect on long-term disability
Potential to further enhance efficacy and
ease of use
GA
IFN
Fingolimod
Natalizumab
Tx-naive
patients
Emerging MS Therapies
114 114
Oral agents
Laquinimod
Teriflunomide
Fumaric acid (BG-12)
Monoclonal antibodies
Daclizumab
Alemtuzumab
Rituximab
Ocrelizumab
Combination therapy
IFN-based
GA-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
115 115
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. Dalfampridine
3
116 116
0%
0% 3. Fingolimod
4. 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. Fingolimod
3
117 117
0%
0% 3. Interferon Beta 1b
4. Interferon Gamma 1a
MB is Experiencing Fatigue and
Depression. Which Drug is a
Good Option for this Patient?
0%
0%
1. Amitriptyline
2. Mirtazapine
3
118 118
0%
0% 3. Imipramine
4. Fluoxetine
RP is Complaining of Problems
Walking. You Recommend Which
of the Following Drugs at add to
his Multiple Sclerosis Therapy?
0%
0% 1. Dalfampridine
2. Bupropion
3
119 119
0%
0% 3. Modafinil
4. Natalizumab
Which Option Below has Proven
to Promote Adherence in Multiple
Sclerosis Patients
0%
0%
0% 1. Set realistic expectations
2. Nonadherence is not a problem
3 Give a drug holiday
120 120
0%
0%
3. Give a drug holiday
4. Defer the drug copay

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