Transcript Slide 1

Challenges and Opportunities for
Managed Care Pharmacists in
Managing Multiple Sclerosis
Robert J. Lipsy, PharmD, BCPS, FASHP
Assistant Professor
University of Arizona
College of Pharmacy
Tucson, Arizona
ARS Question:
Disease modifying therapies for multiple
sclerosis have been shown to do which of
the following?
1)
Reduce the frequency of exacerbations and the
progression of CNS disease burden
2)
Eliminate exacerbations and the progression of
CNS disease burden
3)
Reduce the frequency of exacerbations and
progression of CNS disease burden and reverse
disability due to CNS disease
4)
Reduce the intensity and duration of
exacerbations
ARS Question:
Factors the can negatively affect
medication adherence in MS include
which of the following?
1)
Needle phobia, adverse reactions, and perceived
lack of efficacy
2)
Needle phobia, adverse reactions, perceived
lack of efficacy, and MS-related fatigue
3)
Needle phobia, adverse reactions, perceived
lack of efficacy, MS-related fatigue, and cost
4)
Needle phobia, adverse reactions, perceived
lack of efficacy, MS-related fatigue, cost, and
depression
Multiple Sclerosis

Most common chronic disease affecting the central
nervous system in young adults

Approximately 400,000 cases in the United States1
– (Estimates range from 250,000–500,000)

The chances of developing MS are 1:1000 in the
general population2

Estimated 2.5 million cases worldwide3

Highest incidence in Caucasians3,4

Higher incidence in women (>2:1)4

3/4 of cases present between ages 15–45 years
1. National MS Society Information Sourcebook. www.nationalmssociety.org/sourcebook. 2. Frohman EM.
Med Clin North Am. 2003;87:867-897. 3. Compston A, Coles A. Lancet. 2002;359:1221-1231.
4. Hogancamp WE, et al. Mayo Clin Proc. 1997;72:871-878.
Economic Impact of Multiple
Sclerosis

Impact in the work place (MS vs non-MS)
–
–
–

Health-related costs: $35,000/patient/year
–

Higher percentage of employees claiming short- or
long-term disability (21.4% vs 5.2%) (P <.0001)1
More disability days per year (29.8 vs 4.5) (P <.0001)1
Average annual costs for disability $3868 vs $414 US
(P <.0001)1
Total cost to US economy: $16 billion/year2
MS is leading cause of disability in young
women and the 2nd leading cause of disability in
young men in the United States
1. Ivanova JI, et al. Pharmacoecomonics. 2009;27:681-691 2. Edlin M, Sonnenreich MA. PT.
2008;33:611-614.
Potential Triggers for MS
Genetic
predisposition
Infectious agent
Abnormal immunologic response
Environmental
factors
MS
Graphics courtesy of Dr. Robert J. Lipsy.
Gilden DH. Lancet Neurol. 2005;4:195-202. Noseworthy JH, et al. N Engl J Med. 2000;343:938-952.
Multiple Sclerosis

An immune-mediated disease
in genetically susceptible
individuals

Dual nature: inflammatory and
neurodegenerative

Demyelination leads to slower
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
©2008 Partners Harvard Medical International.
Trapp BD, et al. N Engl J Med. 1998;338:278-285. Gordon-Lipkin, et al. Neurology. 2007;69:1603-1609.
Types of Multiple Sclerosis (MS)



Relapsing-remitting
(RRMS)
Secondaryprogressive (SPMS)
Primary-progressive
(PPMS)
Progressive-relapsing
(PRMS)
Relapsing-remitting
Disability

Secondary-progressive
Primary-progressive
Progressive-relapsing
Time
Graphic courtesy of Dr. Robert J. Lipsy.
Lublin FD, Reingold SC. Neurology. 1998;46:907-911.
Untreated Multiple Sclerosis
Silent Phase
Relapsing & Remitting
Early
Visible
Secondary Progressive
Late
Progression and
axonal loss
Invisible
MRI Activity
MRI=magnetic resonance imaging
Reprinted with permission from the Multiple Sclerosis Foundation
Treatment delays progression!
Silent Phase
Relapsing & Remitting
Early
Visible
Secondary Progressive
Late
Progression and
axonal loss
Invisible
MRI Activity
MRI=Magnetic resonance imaging
Reprinted with permission from the Multiple Sclerosis Foundation
Approach to Therapy

Treatment of acute exacerbations

Modification of disease progression

Management of disease signs and symptoms
Acute Exacerbations

Signs and symptoms for a minimum
of 48–72 hours

Return to baseline by 3 months

Anti-inflammatory therapies can reduce
inflammation in brain and spinal cord

There may be relief of signs and symptoms,
including severity and duration

Corticosteroids (eg, methylprednisolone,
prednisone, dexamethasone)

Adrenocorticotropin hormone (ACTH)

Intravenous immunoglobulin (IVIG)
Disease-Modifying Therapies

Prolong time to clinically definite multiple
sclerosis (CDMS) in patients with clinically
isolated syndrome (CIS)

Decrease the number of patients with CIS who
develop CDMS

Prolong time to subsequent relapses and
sustained disability in patients with RRMS

Reduce frequency of exacerbations in RRMS

Reduce the number of patients who develop
sustained disability
7 Approved Disease-Modifying
Therapies
First-line
therapies
Second-line
therapy
Worsening/
progressive
disease
IM IFNβ-1a
SC IFNβ-1a
SC IFNβ-1b
Glatiramer acetate
Fingolimod
Natalizumab
Mitoxantrone
Graphic courtesy of Dr. Robert J. Lipsy.
Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.
FDA-Approved Therapies for MS
Parenteral Immunomodulators
Agents*
Doses and Administration
Glatiramer acetate1
(Copaxone®)
Indications
CIS
RRMS
Low-dose IFNβ-1a2
(Avonex®)
CIS
RRMS
30 mcg/wk IM
High-dose IFNβ-1a3
(Rebif®)
RRMS
CIS†
22 mcg or 44 mcg TIW SC
High-dose IFNβ-1b4,5
(Betaseron®, Extavia®)
CIS
RRMS
250 mcg QOD SC
20 mg/d SC
*Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way
endorses the use of the product with the trade name.
†Pending FDA approval (REFLEX trial).
1. Glatiramer acetate (Copaxone®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf.
2. Low-dose IFNβ-1a (Avonex®). www.accessdata.fda.gov/drugsatfda_docs/label/2007/103628s5115lbl.pdf.
3. High-dose IFNβ-1a (Rebif®). www.accessdata.fda.gov/drugsatfda_docs/label/2005/103780s5062lbl.pdf.
4. High-dose IFNβ-1b (Betaseron®). www.accessdata.fda.gov/drugsatfda_docs/label/2003/103471s5032lbl.pdf.
5. High-dose IFNβ-1b (Extavia®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/125290s0000lbl.pdf.
FDA-Approved Therapies for MS
Parenteral Immunosuppressive
Agents*
Natalizumab1
(Tysabri®) †
Mitoxantrone2
(Novantrone®) ††
Indications
Doses and
Administration
Relapsing forms of MS
300 mg q4wk IV
SPMS, PRMS,
Worsening RRMS
12 mg/m2 over 5–15 min
q3mo IV infusion
*Trade names are included in this presentation to reduce confusion regarding medication formulations
and in no way endorses the use of the product with the trade name.
†Currently used as 2nd-line therapy.
††Only indicated for progressive and/or worsening disease; cumulative dose should not exceed
140 mg/m2.
1. Natalizumab (Tysabri®). www.accessdata.fda.gov/drugsatfda_docs/label/2008/125104s106lbl.pdf
2. Mitoxantrone (Novantrone®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/
019297s030s031lbl.pdf
Newly Approved Oral MS Therapies
Disease-Modifying Therapy
Fingolimod (FTY720)
Mechanisms of Action
Sphingosine-1P (S-1P) receptor
agonist
Blocks lymphocyte migration
Symptomatic Management
Fampridine
Mechanisms of Action
Blocks voltage-dependent
K+ channels
May restore conduction in poorly
myelinated nerve fibers
Emerging MS Therapies
Tx-naive
patients
GA
IFNb
First-line therapies
Consistent effect on relapses and MRI Fingolimod
Further optimization of dose and frequency
Unclear effect on long-term disability
Potential to further enhance efficacy and ease of use
Main emerging therapies and strategies
Oral agents
Cladribine
Laquinimod
Teriflunomide
Fumaric acid
Monoclonal antibodies
Daclizumab
Alemtuzumab
Rituximab
Ocrelizumab
Combination therapy
IFNb-based
GA-based
Novel agents
MS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at:
http://www.msforum.net/Site/Slide-Sets-And-CD-Roms/
Abbreviations: GA, glatiramer acetate; IFNb, interferon beta.
MS Therapies in Late-Stage Clinical
Development—Oral Agents
DMTs
Cladribine
Mechanisms of Action
Purine nucleoside analog
Preferentially depletes lymphocytes
Dimethyl fumarate (BG12) May have both anti-inflammatory and
neuroprotective properties
Laquinimod
(ABR-215062)
Believed to alter balance of Th1 and
Th2 lymphocyte and cytokine profiles
Teriflunomide
Dihydro-orotate dehydrogenase
inhibitor
Blocks pyrimidine synthesis
MS Therapies in Late-Stage Clinical
Development—Monoclonal Antibodies
Agent
Mechanisms of Action
Alemtuzumab
Anti-CD52
Depletes T and B lymphocytes
Daclizumab
Anti-CD25 (IL-2 receptor α-chain)
Inhibits T lymphocyte activation and
expansion
Anti-CD20
Deplete B lymphocytes
Rituximab/
ocrelizumab
Patient Adherence to MS Medication

MS poses unusual challenges to adherence
– Needle phobia
– New daily routines
– Perceived lack of efficacy

According to adherence studies
– Many patients display new or increased depression within
6 months of treatment initiation1



Depressed patients displayed decreased adherence1
Treating depression may prevent treatment discontinuation1
Most frequent cause of stopping treatment is
perceived lack of efficacy2
– Most treatment withdrawals occur within 1st year of
treatment2

Side effects and tolerability issues can result in
nonadherence or discontinuation of medications
1. Mohr DC, et al. Arch Neurol. 1997;54:531-533. 2. Clerico M, et al. J Neurol Sci. 2007;259:104-108.
Nonadherence to MS DiseaseModifying Therapies
Time Frame
% of Nonadherent
Patients
6 months
12.9
Milanese et al (2003)
3 years
15.3–41.1
Ruggieri et al (2003)
5 years
39.3
Tremlett & Oger (2003)
6 months
27
Fraser et al (2004)
6 months
21.2
2 years
30.2
6 months
12.9
4 years
45.8
Study
Mohr et al (2001)
Haas & Firzlaff (2005)
Turner et al (2007)
Portaccio et al (2008)
With permission from Klauer T, Zettl UK. J Neurol. 2008;255(suppl 6):87–92.
Adherence


Between 17% and 40% of patients stop
taking disease-modifying drugs within 1
year of initiation1-3
Multifactorial
– Perceived lack of efficacy1,2
– Adverse effects2,3
– Depression


Within 6 months of treatment initiation, 41% of patients
had new or increased depression4
Decreased adherence in patients with untreated
depression4
1. Clerico M, et al. J Neurol Sci. 2007;259:104-108. 2. Rio J, et al. Mult Scler. 2005;11:306-309.
3. Daugherty KK, et al. J Am Pharm Assoc. 2005;45:371-375. 4. Mohr DC, et al. Arch Neurol.
1997;54:531-533.
Studies of Patient Adherence
to MS Medications

Longitudinal, prospective study of 199
patients with definite MS
– Of 97 patients taking DMT



73% missed doses
10% missed >10 doses in a 6-month period
25% stopped DMT
– Missed doses were associated with alcohol intake
– History of missed doses predicted future missed
doses
– Numerous and divergent factors influenced
missed doses and stopping DMT

Indicates need for multifaceted approach to improving
adherence
Tremlett H, et al. Pharmacoepidemiol Drug Saf. 2008;17:565-576.
Studies of Patient Adherence
to MS Medications

Spanish study of 632 patients who had
initiated immunomodulatory drugs (IMD)
for MS
– All patients received education on treatment
expectations and side effects
– 17% (107/632) had stopped IMD



More patients with secondary-progressive MS stopped
than relapsing-remitting MS
56 patients stopped because of lack of efficacy
27 patients stopped for reasons unrelated to efficacy or
side effects
– EDSS score at study entry was the main factor
that predicted interruption of therapy
Rio J, et al. Mult Scler. 2005;11:306-309.
Patients in United States Find it
Harder to Pay for Care
Patients stating that they often have difficulty paying
for medications or other care costs
Graphic courtesy of Dr. Robert J. Lipsy.
The Commonwealth Health Fund 2009 International Healthy Policy Survey of Primary Care Doctors.
Health Affairs. 5 November 2009.
Biologic Therapy Adherence and
Patient Costs
High Out-of-Pocket Expenses Associated with Lower
Medication Adherence
Probability of Persisting
1.2
Under $50
Over $50
1
0.8
0.6
0.4
0.2
0
1
3
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51
Weekly Dosing Periods
Univariate Kaplan-Meier curves illustrating persistence on anti-TNF therapy for
patients with out-of-pocket payments over VERSUS under $50 per week.
With permission from Curkendall S, et al. Arthritis Rheum. 2008;59:1519-1526.
Anti-TNF Prescription Abandonment
As out-of-pocket expenses increase, treatment abandonment increases
With permission from Gleason PP, et al. J Manag Care Pharm. 2009;15:648-658.
Promoting Adherence to Therapeutic
Regimens in MS
Establishing Realistic Expectations

Therapies have been shown to reduce 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
–
–
–
–
Only work if patients take them
Are not cures for MS
May not eliminate MS symptoms
Do not completely eliminate future disease activity
Cerghet M, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P05.073.
Putzki N, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P05.076.
Disease-Modifying Therapies

Relapse free at 1 year 51%–80%

Relative decrease in annual relapse rate
30%–80%

Absolute annual relapse rate 0.15–0.7

Relative decrease in sustained
progression 31%–42%

Absolute rate of disease progression
9%–18%
Data courtesy of Dr. Robert J. Lipsy.
Symptoms of MS

Common
 Less Common
– Vision problems
– Headache
– Fatigue
– Hearing loss
– Paresthesia
– Itching
– Bladder, bowel,
– Seizures
sexual dysfunction
– Speech, swallowing
– Gait problems,
difficulties
spasticity
– Tremor,
– Dizziness, vertigo
incoordination
– Pain
– Depression
– Cognitive dysfunction
National Multiple Sclerosis Society. About MS: Symptoms.
http://www.nationalmssociety.org/about-multiple-sclerosis/symptoms/index.asp.
Multidisciplinary Team Approach
Neurologist
Pharmacist
Physical Therapist
Nurse/APN
Primary Care
Physician
Psychiatrist
Psychologist/
Neuropsychologist
Patient
Occupational
Therapist
Orthopedist
Vocational
Counselor
Social Worker
Urologist
Speech Pathologist
Physiatrist
ARS Question:
Disease modifying therapies for multiple
sclerosis have been shown to do which of
the following?
1)
Reduce the frequency of exacerbations and the
progression of CNS disease burden
2)
Eliminate exacerbations and the progression of
CNS disease burden
3)
Reduce the frequency of exacerbations and
progression of CNS disease burden and reverse
disability due to CNS disease
4)
Reduce the intensity and duration of
exacerbations
ARS Question #1 PRE:
Disease modifying therapies for multiple sclerosis have
been shown to do which of the following?
1)
Reduce the frequency of exacerbations and the
progression of CNS disease burden
80.0%
2)
Eliminate exacerbations and the progression of CNS
disease burden
4.2%
3)
Reduce the frequency of exacerbations and
progression of CNS disease burden and reverse
disability due to CNS disease
0.0%
4)
Reduce the intensity and duration of exacerbations
15.8%
ARS Question #1 POST:
Disease modifying therapies for multiple sclerosis have
been shown to do which of the following?
1)
Reduce the frequency of exacerbations and the
progression of CNS disease burden
90.0%
2)
Eliminate exacerbations and the progression of CNS
disease burden
0.0%
3)
Reduce the frequency of exacerbations and
progression of CNS disease burden and reverse
disability due to CNS disease
10.0%
4)
Reduce the intensity and duration of exacerbations
0.0%
ARS Question:
Factors the can negatively affect
medication adherence in MS include
which of the following?
1)
Needle phobia, adverse reactions, and perceived
lack of efficacy
2)
Needle phobia, adverse reactions, perceived
lack of efficacy, and MS-related fatigue
3)
Needle phobia, adverse reactions, perceived
lack of efficacy, MS-related fatigue, and cost
4)
Needle phobia, adverse reactions, perceived
lack of efficacy, MS-related fatigue, cost, and
depression
ARS Question #2 PRE :
Factors the can negatively affect medication adherence
in MS include which of the following?
1)
Needle phobia, adverse reactions, and perceived
lack of efficacy
3.7%
2)
Needle phobia, adverse reactions, perceived lack of
efficacy, and MS-related fatigue
0.0%
3)
Needle phobia, adverse reactions, perceived lack of
efficacy, MS-related fatigue, and cost
0.0%
4)
Needle phobia, adverse reactions, perceived lack of
efficacy, MS-related fatigue, cost, and depression
96.3%
ARS Question #2 POST:
Factors the can negatively affect medication adherence
in MS include which of the following?
1)
Needle phobia, adverse reactions, and perceived
lack of efficacy
0.0%
2)
Needle phobia, adverse reactions, perceived lack of
efficacy, and MS-related fatigue
0.0%
3)
Needle phobia, adverse reactions, perceived lack of
efficacy, MS-related fatigue, and cost
0.0%
4)
Needle phobia, adverse reactions, perceived lack of
efficacy, MS-related fatigue, cost, and depression
100.0%
Common Issues Facing Patients
with Multiple Sclerosis
Jacquelyn L. Bainbridge, PharmD, FCCP
Professor
Departments of Clinical Pharmacy and Neurology
University of Colorado Denver
Aurora, Colorado
ARS Question:
In a patient with fatigue and depression,
which of the following would be the most
appropriate treatment option?
1)
Tricyclic antidepressants (TCA’s)
2)
Fluoxetine (this is correct)
3)
Paroxetine
4)
Mirtazapine
ARS Question:
Which of the following drugs used to treat
over-active bladder is associated with the
lowest incidence of cognitive dysfunction
adverse events?
1)
Oxybutynin
2)
Tolterodine
3)
Trospium
4)
Darifenacin (this is the correct answer)
Common Issues Facing Patients with
Multiple Sclerosis

Decreased cognition

Depression

Bladder dysfunction

Neuropathic pain
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 remember1
5%–10% of patients suffer from moderate
to severe cognitive impairment1
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 attention2
1.National Multiple Sclerosis Society. www.nationalmssociety.org/about-multiple-sclerosis/what-weknow-about-ms/symptoms/cognitive-function/index.aspx.
2. 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)
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)
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
multidrug ones
Attempt to use drugs for >1 use
Cognition and Atrophy
Graphic courtesy of Dr. J. Bainbridge.
22-Year-Old Female
Diagnosed at 15 Years of Age
Graphic courtesy of Dr. J. Bainbridge.
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)
– Related to the neuropathology of MS
– Interferons may precipitate or worsen

Relationship between fatigue/depression
– Fatigue
Depression
– Depression
Fatigue
O’Conner 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

Consider comorbidities when selecting agent
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
Treating Depression
Comorbid Conditions






Insomnia
Mirtazapine, TCAs
Neuropathy
Duloxetine, TCAs
Sexual dysfunction
Bupropion
Fatigue
SNRIs, fluoxetine, stimulants
Cognition/balance
Avoid TCAs
Incontinence
SNRIs, TCAs
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and 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

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)
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
Treating Depression
Patient Counseling Tips





Benefits take 6–8 weeks
Treatment duration varies
Treatment failure anticipated
Suicide is 7 times more common than
in the general population
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
– 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 Dysfunction
Nonpharmacologic and Prophylactic
Treatments

Hyporeflexive bladder (failure to empty)
–
Crede maneuver, timed voids, catheterization

Long-term complications
–
–
Urinary tract infections (UTIs)
Urosepsis

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
Pharmacologic Treatments

Failure to empty (hyporeflexive bladder)
– Cholinergic agents (bethanechol chloride)

Nocturia
– Desmopressin acetate (DDAVP)
Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.
Bladder Dysfunction
Pharmacologic 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

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®):
1 g daily
Tolterodine (Detrol®):
1–2 mg twice daily – w/3A4
inhibitor, decrease dose
Tolterodine LA (Detrol LA®):
2–4 mg daily
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
metabolized
Trospium XR (Sanctura XR®):
60 mg daily
Solifenacin (Vesicare®):
5–10 mg daily
Darifenacin (Enablex®):
7.5–15 mg daily
Trade names are included in this presentation to reduce confusion regarding medication
formulations and in no way endorses the use of the product with the trade name.
Abbreviations: OAB, overactive bladder; UI, urinary incontinence.
Comparison of OAB Agents
Dry Mouth
(%)
Constipation
(%)
Dizziness
(%)
Vision
Changes
(%)
Oxybutynin
85
40
32
20
Oxy ER/XL
35
7
5
2
Oxy TDS
7
3
1
1
Oxy gel
8
1
3
?
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
Drug
Tolterodine
Abbreviation: OAB, overactive bladder.
Differentiation of Muscarinic
Receptors in the Central Nervous
System





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 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
Patient 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
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
O’Conner 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, L’Hermitte’s sign, face twitching
Carbamazepine 200 mg PO BID or TID
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.
Summary





Decreased or impaired cognition, depression,
bladder dysfunction and pain syndromes are
common in patients with MS
It is essential that a neurologist trained in MS
evaluates, treats and manages patients in order
to achieve optimal outcomes
The pharmacist should realize that MS is a
complex disease state involving many types
of therapies
It is important to optimize therapy, using a single
agent to treat multiple symptoms when possible
Assess patients and their therapies often to avert
enhancement of underlying symptoms
ARS Question:
In a patient with fatigue and depression,
which of the following would be the most
appropriate treatment option?
1)
Tricyclic antidepressants (TCA’s)
2)
Fluoxetine (this is correct)
3)
Paroxetine
4)
Mirtazapine
ARS Question #1 PRE :
In a patient with fatigue and depression, which of the
following would be the most appropriate treatment
option?
1)
Tricyclic antidepressants (TCA’s)
18.8%
2)
Fluoxetine
43.8%
3)
Paroxetine
25.0%
4)
Mirtazapine
23.5%
ARS Question #1 POST:
In a patient with fatigue and depression, which of the
following would be the most appropriate treatment
option?
1)
Tricyclic antidepressants (TCA’s)
9.1%
2)
Fluoxetine
90.9%
3)
Paroxetine
0.0%
4)
Mirtazapine
0.0%
ARS Question:
Which of the following drugs used to treat
over-active bladder is associated with the
lowest incidence of cognitive dysfunction
adverse events?
1)
Oxybutynin
2)
Tolterodine
3)
Trospium
4)
Darifenacin (this is the correct answer)
ARS Question #2 PRE :
Which of the following drugs used to treat over-active
bladder is associated with the lowest incidence of
cognitive dysfunction adverse events?
1)
Oxybutynin
28.6%
2)
Tolterodine
25.0%
3)
Trospium
7.1%
4)
Darifenacin
39.3%
ARS Question #2 POST:
Which of the following drugs used to treat over-active
bladder is associated with the lowest incidence of
cognitive dysfunction adverse events?
1)
Oxybutynin
14.3%
2)
Tolterodine
14.3%
3)
Trospium
0.0%
4)
Darifenacin
71.4%
Common Issues Facing Patients
with Multiple Sclerosis
Ellen Whipple Guthrie, BS Pharm, PharmD
Clinical Assistant Professor
University of Georgia College of Pharmacy
Medical Advisory Board
Multiple Sclerosis Foundation
Marietta, Georgia
ARS Question:
RE is a 43YO patient with MS. RE has been taking
baclofen 20 mg FOUR times per day for spasticity.
RE is out of medication. The pharmacy will not have
the medication in stock for 3 days. What advice to
you have for RE?
1)
Baclofen withdrawal can be very dangerous
2)
Patients should never just stop taking baclofen
without talking to their prescriber
3)
The patients hair could fall out because he
stopped taking baclofen “cold turkey”
4)
1 and 2
ARS Question:
Which of the following statement about
dalfampridine is true?
1)
Dalfampridine is the 1st approved product for
MS to help with cognitive impairment
2)
Dalfampridine contains the same active
ingredient as 4-aminopyridine
3)
Dalfampridine and 4-aminopyridine can be
interchanged (substituted for each other)
Common Issues Facing Patients with
Multiple Sclerosis

Spasticity

Walking/mobility issues

Fatigue

Sexual dysfunction
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, stiffness, tremor, clonus, impaired balance,
and spasms
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
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 ulcers, poorly fitting
assistive living devices)2,3

IFN-b 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 offers some limb stabilization
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
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
temperature be approximately 85oF (warmer
temperatures cause fatigue; colder temperatures
exacerbate spasticity)
Mechanical aids
– Orthotics
– Braces
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227255. Henze T. Int MS J. 2007;14:22-27. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.
Spasticity
Pharmacologic 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
and confusion
– AEs decrease over time
– Avoid suddenly stopping the drug
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
Spasticity
Pharmacologic Treatments

Second-line agents; frequently used in
combination with oral baclofen
–
–
–
–
–

Tizanidine
Diazepam
Clonazepam
Dantrolene
Clonidine
Refractory spasticity
– Botulinum toxin
– Intrathecal baclofen
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:227255. Henze T. Int MS J. 2007;14:22-27. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.
Spasticity
Patient 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
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!
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
Walking/Mobility Issues

Gait disturbances are a common
symptomatic problem

Extended Disability Status Scale (EDSS)
scoring used to assess walking mobility
issues
EDSS Scoring
Available at: www.msdecisions.org.uk.
Kurtzke JF, et al. Neurology. 1983;33:1442-1452.
Walking/Mobility Issues

Traditionally have been managed using
nonpharmacologic treatments (ie, exercise,
physical therapy, gait training, assistive
devices)
Walking/Mobility Issues

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
– 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

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 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.
Dalfampridine
Patient 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 (keeping 12 hours between doses
to prevent adverse events)
Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.
Dalfampridine
Patient 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 taking compounded
4-aminopyridine, should not take
dalfampridine
Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.
Dalfampridine
vs 4-Aminopyridine

Not bioequivalent

Cannot be substituted

Dalfampridine only indicated for
walking/mobility issues
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
– 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
–
–
–
–
–
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 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 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
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
Treating Fatigue
Pharmacologic Treatments

Modafinil1-3
–
–

4-aminopyridine1-3
–
–

5–20 mg twice daily (AM and in the early afternoon)
Especially effective in treating heat-related fatigue
Selective serotonin reuptake inhibitors (ie,
fluoxetine)1,2
–
–

100–400 mg once daily in the AM
First-line agent for improving daytime fatigue
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 Fatigue
Patient 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
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
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

Tricyclic antidepressants
Henze T. Int MS J. 2007;14:22-27. O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases.
Lippincott, Williams, and Wilkins; 2006:227-255. Crayton H, et al. Neurology. 2004;63(11 suppl 5): S1218.
Treating Sexual Dysfunction in Males

First line
– Phosphodiesterase inhibitors (eg, sildenafil)1-4

Second line
– Alprostadil injections
– Amantadine
– 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
O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins;
2006:227-255.
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
Effective management of MS-related symptoms
requires a coordinated, multidisciplinary approach
that includes pharmacists, physical therapists,
psychologists, and neurologists
Pharmacists 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
ARS Question:
RE is a 43YO patient with MS. RE has been taking
baclofen 20 mg FOUR times per day for spasticity.
RE is out of medication. The pharmacy will not have
the medication in stock for 3 days. What advice to
you have for RE?
1)
Baclofen withdrawal can be very dangerous
2)
Patients should never just stop taking baclofen
without talking to their prescriber
3)
The patients hair could fall out because he
stopped taking baclofen “cold turkey”
4)
1 and 2
ARS Question #1 PRE :
RE is a 43YO patient with MS. RE has been taking baclofen
20 mg FOUR times per day for spasticity. RE is out of
medication. The pharmacy will not have the medication in
stock for 3 days. What advice to you have for RE?
1)
Baclofen withdrawal can be very dangerous
0.0%
2)
Patients should never just stop taking baclofen
without talking to their prescriber
4.6%
3)
The patients hair could fall out because he stopped
taking baclofen “cold turkey”
18.2%
4)
1 and 2
77.3%
ARS Question #1 POST:
RE is a 43YO patient with MS. RE has been taking baclofen
20 mg FOUR times per day for spasticity. RE is out of
medication. The pharmacy will not have the medication in
stock for 3 days. What advice to you have for RE?
1)
Baclofen withdrawal can be very dangerous
6.3%
2)
Patients should never just stop taking baclofen
without talking to their prescriber
0.0%
3)
The patients hair could fall out because he stopped
taking baclofen “cold turkey”
0.0%
4)
1 and 2
93.8%
ARS Question:
Which of the following statement about
dalfampridine is true?
1)
Dalfampridine is the 1st approved product for
MS to help with cognitive impairment
2)
Dalfampridine contains the same active
ingredient as 4-aminopyridine
3)
Dalfampridine and 4-aminopyridine can be
interchanged (substituted for each other)
ARS Question #2 PRE :
Which of the following statement about
dalfampridine is true?
1)
Dalfampridine is the 1st approved product for MS to
help with cognitive impairment
31.8%
2)
Dalfampridine contains the same active ingredient
as 4-aminopyridine
50.0%
3)
Dalfampridine and 4-aminopyridine can be
interchanged (substituted for each other)
18.2%
ARS Question #2 POST:
Which of the following statement about
dalfampridine is true?
1)
Dalfampridine is the 1st approved product for MS to
help with cognitive impairment
14.3%
2)
Dalfampridine contains the same active ingredient
as 4-aminopyridine
81.0%
3)
Dalfampridine and 4-aminopyridine can be
interchanged (substituted for each other)
4.7%