Challenges and Opportunities for Managed Care Pharmacists in Managing Multiple Sclerosis Robert J. Lipsy, PharmD, BCPS, FASHP Assistant Professor University

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?





ARS Question #1 PRE:Disease modifying therapies for multiple sclerosis have

been shown to do which of the following?





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?





90.0%

0.0%

10.0%

0.0%

ARS Question:Factors the can negatively affect

medication adherence in MS include which of the following?





ARS Question #2 PRE :Factors the can negatively affect medication adherence

in MS include which of the following?





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?





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)


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


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)


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


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?


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?


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?


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%


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)


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


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


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


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!


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


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


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)


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


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


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


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?




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?




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?




4) 1 and 2

6.3%

0.0%

0.0%

93.8%

ARS Question:Which of the following statement about





ARS Question #2 PRE :Which of the following statement about





18.2%

50.0%

31.8%

ARS Question #2 POST:Which of the following statement about





14.3%

81.0%

4.7%

Documents

Challenges and Opportunities for Managed Care Pharmacists in Managing Multiple Sclerosis Robert J. Lipsy, PharmD, BCPS, FASHP Assistant Professor University