Challenges and Opportunities for Managed Care Pharmacists in Managing Multiple Sclerosis Robert J....
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Transcript of Challenges and Opportunities for Managed Care Pharmacists in Managing Multiple Sclerosis Robert J....
Challenges and Opportunities for Managed Care Pharmacists in Managing Multiple Sclerosis
Robert J. Lipsy, PharmD, BCPS, FASHP
Assistant ProfessorUniversity 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
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.
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
Economic Impact of Multiple Sclerosis
Impact in the work place (MS vs non-MS)– 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
Health-related costs: $35,000/patient/year– 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
Environmentalfactors
Abnormal immunologic response
Genetic predisposition
Infectious agent
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.
Trapp BD, et al. N Engl J Med. 1998;338:278-285. Gordon-Lipkin, et al. Neurology. 2007;69:1603-1609.
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.
Types of Multiple Sclerosis (MS)
Relapsing-remitting (RRMS)
Secondary-progressive (SPMS)
Primary-progressive (PPMS)
Progressive-relapsing (PRMS)
D
isa
bili
ty
Time
Relapsing-remitting
Secondary-progressive
Progressive-relapsing
Primary-progressive
Graphic courtesy of Dr. Robert J. Lipsy.Lublin FD, Reingold SC. Neurology. 1998;46:907-911.
Silent Phase Relapsing & Remitting Secondary Progressive
Untreated Multiple Sclerosis
Early Late
Progression and axonal loss
Invisible
Reprinted with permission from the Multiple Sclerosis Foundation
MRI Activity
Visible
MRI=magnetic resonance imaging
Progression and axonal loss
Silent Phase Relapsing & Remitting Secondary Progressive
Treatment delays progression!
Early Late
MRI ActivityReprinted with permission from the Multiple Sclerosis Foundation
Invisible
Visible
MRI=Magnetic resonance imaging
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-linetherapy
Worsening/progressive disease
IM IFNβ-1a SC IFNβ-1aSC IFNβ-1bGlatiramer acetateFingolimod
Natalizumab
Mitoxantrone
Graphic courtesy of Dr. Robert J. Lipsy. Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.
FDA-Approved Therapies for MSParenteral Immunomodulators
Agents* IndicationsDoses and Administration
Glatiramer acetate1 (Copaxone®)
CIS RRMS
20 mg/d SC
Low-dose IFNβ-1a2 (Avonex®)
CISRRMS
30 mcg/wk IM
High-dose IFNβ-1a3 (Rebif®)
RRMSCIS†
22 mcg or 44 mcg TIW SC
High-dose IFNβ-1b4,5 (Betaseron®, Extavia®)
CIS RRMS
250 mcg QOD 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* IndicationsDoses and
Administration
Natalizumab1 (Tysabri®) †
Relapsing forms of MS
300 mg q4wk IV
Mitoxantrone2
(Novantrone®)
††
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.pdf2. Mitoxantrone (Novantrone®). www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 019297s030s031lbl.pdf
Newly Approved Oral MS Therapies
Disease-Modifying Therapy
Mechanisms of Action
Fingolimod (FTY720) Sphingosine-1P (S-1P) receptor agonist
Blocks lymphocyte migration
Symptomatic Management
Mechanisms of Action
Fampridine Blocks voltage-dependent K+ channels
May restore conduction in poorly myelinated nerve fibers
First-line therapies
Consistent effect on relapses and MRIFurther optimization of dose and frequency
Unclear effect on long-term disabilityPotential to further enhance efficacy and ease of use
Oral agents Cladribine Laquinimod
Teriflunomide Fumaric acid
Monoclonal antibodies
DaclizumabAlemtuzumab
RituximabOcrelizumab
Combination therapy
IFN-basedGA-based
Novel agents
Main emerging therapies and strategies
GAIFN
Fingolimod
Tx-naive patients
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; IFN, interferon beta.
Emerging MS Therapies
MS Therapies in Late-Stage Clinical Development—Oral Agents
DMTs Mechanisms of Action Cladribine 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-CD52Depletes T and B lymphocytes
Daclizumab Anti-CD25 (IL-2 receptor α-chain)Inhibits T lymphocyte activation and expansion
Rituximab/ocrelizumab
Anti-CD20 Deplete B lymphocytes
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 Disease-Modifying Therapies
Study Time Frame% of Nonadherent
Patients
Mohr et al (2001) 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
Haas & Firzlaff (2005) 2 years 30.2
Turner et al (2007) 6 months 12.9
Portaccio et al (2008) 4 years 45.8
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 payingfor 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
With permission from Curkendall S, et al. Arthritis Rheum. 2008;59:1519-1526.
Univariate Kaplan-Meier curves illustrating persistence on anti-TNF therapy for patients with out-of-pocket payments over VERSUS under $50 per week.
High Out-of-Pocket Expenses Associated with Lower Medication Adherence
0
0.2
0.4
0.6
0.8
1
1.2
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
Pro
ba
bili
ty o
f P
ers
isti
ng
Under $50
Over $50
Anti-TNF Prescription AbandonmentAs 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 activityCerghet 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
– Vision problems– Fatigue– Paresthesia– Bladder, bowel,
sexual dysfunction– Gait problems,
spasticity– Dizziness, vertigo– Pain– Depression– Cognitive dysfunction
Less Common– Headache– Hearing loss– Itching– Seizures– Speech,
swallowing difficulties
– Tremor, incoordination
National Multiple Sclerosis Society. About MS: Symptoms. http://www.nationalmssociety.org/about-multiple-sclerosis/symptoms/index.asp.
Primary Care Physician
Neurologist
Nurse/APN
Occupational Therapist
Physical Therapist
Social Worker
Psychologist/Neuropsychologist
Speech Pathologist
UrologistOrthopedist
Psychiatrist
Pharmacist
Vocational Counselor
Patient
Multidisciplinary Team Approach
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
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
80.0%
15.8%
4.2%
0.0%
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
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
90.0%
0.0%
10.0%
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
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
3.7%
96.3%
0.0%
0.0%
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
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
0.0%
0.0%
0.0%
100.0%
Common Issues Facing Patients with Multiple Sclerosis
Jacquelyn L. Bainbridge, PharmD, FCCP
ProfessorDepartments of Clinical Pharmacy and
NeurologyUniversity 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-we-know-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 FatigueO’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. 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
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, 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 DepressionPatient 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 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 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 DysfunctionNonpharmacologic 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– CinoxacinSchapiro 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)
Goldman MD, et al. Cleve Clin J Med. 2006;73:177-186.
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.
Bladder DysfunctionPharmacologic Treatments
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
Abbreviations: OAB, overactive bladder; UI, urinary incontinence.
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.
Comparison of OAB Agents
DrugDry Mouth
(%)Constipation
(%)Dizziness
(%)
VisionChanges
(%)
Oxybutynin 85 40 32 20
Oxy ER/XL 35 7 5 2
Oxy TDS 7 3 1 1
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
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 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– 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)
2) Fluoxetine
3) Paroxetine
4) Mirtazapine
25.0%
23.5%
43.8%
18.8%
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)
2) Fluoxetine
3) Paroxetine
4) Mirtazapine
9.1%
90.9%
0.0%
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
2) Tolterodine
3) Trospium
4) Darifenacin39.3%
7.1%
25.0%
28.6%
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
2) Tolterodine
3) Trospium
4) Darifenacin
14.3%
14.3%
0.0%
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 BoardMultiple 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- 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.
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 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; 2006:227-255. 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
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; 2006:227-255. 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 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
Available at: www.msdecisions.org.uk. Kurtzke JF, et al. Neurology. 1983;33:1442-1452.
EDSS Scoring
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.
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 (keeping 12 hours between doses to prevent adverse events)
Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.
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 taking compounded 4-aminopyridine, should not take dalfampridine
Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.
Dalfampridinevs 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 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 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 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)– 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 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): S12-18.
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
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
77.3%
0.0%
4.6%
18.2%
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
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
6.3%
0.0%
0.0%
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
2) Dalfampridine contains the same active ingredient as 4-aminopyridine
3) Dalfampridine and 4-aminopyridine can be interchanged (substituted for each other)
18.2%
50.0%
31.8%
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
2) Dalfampridine contains the same active ingredient as 4-aminopyridine
3) Dalfampridine and 4-aminopyridine can be interchanged (substituted for each other)
14.3%
81.0%
4.7%