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

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Presentation on theme: "Challenges and Opportunities for Managed Care Pharmacists in Managing Multiple Sclerosis Robert J. Lipsy, PharmD, BCPS, FASHP Assistant Professor University."— Presentation transcript:

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2 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

3 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

4 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

5 1. National MS Society Information Sourcebook. 2. Frohman EM. Med Clin North Am. 2003;87: Compston A, Coles A. Lancet. 2002;359: Hogancamp WE, et al. Mayo Clin Proc. 1997;72: Multiple Sclerosis Most common chronic disease affecting the central nervous system in young adults Approximately 400,000 cases in the United States 1 –(Estimates range from 250,000–500,000) The chances of developing MS are 1:1000 in the general population 2 Estimated 2.5 million cases worldwide 3 Highest incidence in Caucasians 3,4 Higher incidence in women (>2:1) 4 3/4 of cases present between ages 15–45 years

6 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/year 2 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: Edlin M, Sonnenreich MA. PT. 2008;33:

7 Potential Triggers for MS Environmental factors Abnormal immunologic response Genetic predisposition Infectious agent MS Graphics courtesy of Dr. Robert J. Lipsy. Gilden DH. Lancet Neurol. 2005;4: Noseworthy JH, et al. N Engl J Med. 2000;343:

8 Trapp BD, et al. N Engl J Med. 1998;338: Gordon-Lipkin, et al. Neurology. 2007;69: 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.

9 Types of Multiple Sclerosis (MS) Relapsing-remitting (RRMS) Secondary-progressive (SPMS) Primary-progressive (PPMS) Progressive-relapsing (PRMS) Disability Time Relapsing-remitting Secondary-progressive Progressive-relapsing Primary-progressive Graphic courtesy of Dr. Robert J. Lipsy. Lublin FD, Reingold SC. Neurology. 1998;46:

10 Silent PhaseRelapsing & RemittingSecondary 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

11 Progression and axonal loss Silent PhaseRelapsing & RemittingSecondary Progressive Treatment delays progression! Early Late MRI Activity Reprinted with permission from the Multiple Sclerosis Foundation Invisible Visible MRI=Magnetic resonance imaging

12 Approach to Therapy Treatment of acute exacerbations Modification of disease progression Management of disease signs and symptoms

13 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)

14 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

15 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.

16 FDA-Approved Therapies for MS Parenteral Immunomodulators Agents* Indications Doses and Administration Glatiramer acetate 1 (Copaxone ® ) CIS RRMS 20 mg/d SC Low-dose IFNβ-1a 2 (Avonex ® ) CIS RRMS 30 mcg/wk IM High-dose IFNβ-1a 3 (Rebif ® ) RRMS CIS 22 mcg or 44 mcg TIW SC High-dose IFNβ-1b 4,5 (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 ® ). 2. Low-dose IFNβ-1a (Avonex ® ). 3. High-dose IFNβ-1a (Rebif ® ). 4. High-dose IFNβ-1b (Betaseron ® ). 5. High-dose IFNβ-1b (Extavia ® ).

17 FDA-Approved Therapies for MS Parenteral Immunosuppressive Agents*Indications Doses and Administration Natalizumab 1 (Tysabri ® ) Relapsing forms of MS300 mg q4wk IV Mitoxantrone 2 (Novantrone ® ) SPMS, PRMS, Worsening RRMS 12 mg/m 2 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/m Natalizumab (Tysabri ® ). 2. Mitoxantrone (Novantrone ® ) s030s031lbl.pdf

18 Newly Approved Oral MS Therapies Disease-Modifying TherapyMechanisms of Action Fingolimod (FTY720) Sphingosine-1P (S-1P) receptor agonist Blocks lymphocyte migration Symptomatic ManagementMechanisms of Action Fampridine Blocks voltage-dependent K+ channels May restore conduction in poorly myelinated nerve fibers

19 First-line therapies Consistent effect on relapses and MRI Further optimization of dose and frequency Unclear effect on long-term disability Potential to further enhance efficacy and ease of use Oral agents Cladribine Laquinimod Teriflunomide Fumaric acid Monoclonal antibodies Daclizumab Alemtuzumab Rituximab Ocrelizumab Combination therapy IFN -based GA-based Novel agents Main emerging therapies and strategies GA IFN Fingolimod Tx-naive patients MS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at: Abbreviations: GA, glatiramer acetate; IFN, interferon beta. Emerging MS Therapies

20 MS Therapies in Late-Stage Clinical DevelopmentOral Agents DMTsMechanisms of Action Cladribine Purine nucleoside analog Preferentially depletes lymphocytes Dimethyl fumarate (BG12) May have both anti-inflammatory and neuroprotective properties Laquinimod (ABR ) Believed to alter balance of Th1 and Th2 lymphocyte and cytokine profiles Teriflunomide Dihydro-orotate dehydrogenase inhibitor Blocks pyrimidine synthesis

21 MS Therapies in Late-Stage Clinical DevelopmentMonoclonal Antibodies AgentMechanisms of Action AlemtuzumabAnti-CD52 Depletes T and B lymphocytes DaclizumabAnti-CD25 (IL-2 receptor α-chain) Inhibits T lymphocyte activation and expansion Rituximab/ ocrelizumab Anti-CD20 Deplete B lymphocytes

22 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 initiation 1 Depressed patients displayed decreased adherence 1 Treating depression may prevent treatment discontinuation 1 Most frequent cause of stopping treatment is perceived lack of efficacy 2 –Most treatment withdrawals occur within 1st year of treatment 2 Side effects and tolerability issues can result in nonadherence or discontinuation of medications 1. Mohr DC, et al. Arch Neurol. 1997;54: Clerico M, et al. J Neurol Sci. 2007;259:

23 Nonadherence to MS Disease- Modifying Therapies StudyTime Frame % of Nonadherent Patients Mohr et al (2001)6 months12.9 Milanese et al (2003)3 years15.3–41.1 Ruggieri et al (2003)5 years39.3 Tremlett & Oger (2003)6 months27 Fraser et al (2004)6 months21.2 Haas & Firzlaff (2005)2 years30.2 Turner et al (2007)6 months12.9 Portaccio et al (2008)4 years45.8 With permission from Klauer T, Zettl UK. J Neurol. 2008;255(suppl 6):87–92.

24 Adherence Between 17% and 40% of patients stop taking disease-modifying drugs within 1 year of initiation 1-3 Multifactorial –Perceived lack of efficacy 1,2 –Adverse effects 2,3 –Depression Within 6 months of treatment initiation, 41% of patients had new or increased depression 4 Decreased adherence in patients with untreated depression 4 1. Clerico M, et al. J Neurol Sci. 2007;259: Rio J, et al. Mult Scler. 2005;11: Daugherty KK, et al. J Am Pharm Assoc. 2005;45: Mohr DC, et al. Arch Neurol. 1997;54:

25 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:

26 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:

27 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.

28 Biologic Therapy Adherence and Patient Costs With permission from Curkendall S, et al. Arthritis Rheum. 2008;59: 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

29 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:

30 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. P Putzki N, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P

31 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.

32 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.

33 Primary Care Physician Neurologist Nurse/APN Occupational Therapist Physical Therapist Social Worker Psychologist/ Neuropsychologist Speech Pathologist Urologist Orthopedist Psychiatrist Pharmacist Vocational Counselor Patient Multidisciplinary Team Approach Physiatrist

34 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

35 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%

36 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%

37 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

38 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%

39 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% 100.0%

40 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

41 ARS Question: In a patient with fatigue and depression, which of the following would be the most appropriate treatment option? 1) Tricyclic antidepressants (TCAs) 2) Fluoxetine (this is correct) 3) Paroxetine 4) Mirtazapine

42 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)

43 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!!

44 Cognition ~50% of patients develop cognitive dysfunction, affecting their ability to think, reason, concentrate, or remember 1 5%–10% of patients suffer from moderate to severe cognitive impairment 1 Treatments include behavioral coping strategies, sometimes in combination with cholinesterase inhibitors (eg, donepezil) or stimulants –Donepezil may have modest effects on verbal learning (ability to recall a list of words), memory, and attention 2 1.National Multiple Sclerosis Society. know-about-ms/symptoms/cognitive-function/index.aspx. 2. OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

45 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!

46 Stimulants or Activating Drugs Amantadine (Symmetrel) Methylphenidate (Ritalin) Dextroamphetamine (Dexedrine) Modafinil (Provigil) Fluoxetine (Prozac) Dalfampridine (Ampyra)

47 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

48 Cognition and Atrophy Graphic courtesy of Dr. J. Bainbridge.

49 22-Year-Old Female Diagnosed at 15 Years of Age Graphic courtesy of Dr. J. Bainbridge.

50 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

51 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

52 Treating Depression Comorbid Conditions Insomnia Mirtazapine, TCAs Neuropathy Duloxetine, TCAs Sexual dysfunction Bupropion Fatigue SNRIs, fluoxetine, stimulants Cognition/balance Avoid TCAs Incontinence SNRIs, TCAs OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

53 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) OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

54 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

55 Bladder Dysfunction Bladder dysfunction problems include failure to empty, failure to store, nocturia or a combination 1,2 –Nocturia –Failure to empty (hyporeflexive bladder) Failure to store (hyperreflexive bladder) –The most common bladder problem seen in MS patients 1,2 –Manifests as urinary urgency and frequency and voiding only small amounts of urine 1,2 –Over time, urgency can become more difficult to control and can lead to incontinence 2 –Failure to store/incomplete bladder emptying (sphincter detrusor dyssynergia) May occur more frequently in men Causes hesitancy, retention, and overflow incontinence 1. OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Goldman MD, et al. Cleve Clin J Med. 2006;73:

56 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: Schapiro RT. Neurorehabil Neural Repair. 2002;16: Bainbridge JL, et al. In: Pharmacotherapy: A Pathophysiological Approach. 7th edition. New York, New York: McGraw-Hill; 2008:

57 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:

58 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 problems 1,2 –Relaxes the internal sphincter 1. Goldman MD, et al. Cleve Clin J Med. 2006;73: Schapiro RT. Neurorehabil Neural Repair. 2002;16: Bladder Dysfunction Pharmacologic Treatments

59 TreatmentUrge 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.

60 Comparison of OAB Agents Drug Dry Mouth (%) Constipation (%) Dizziness (%) Vision Changes (%) Oxybutynin Oxy ER/XL35752 Oxy TDS7311 Oxy gel813? Tolterodine61, 2313, 66, 28, 1 Fesoterodine356?? Trospium Solifenacin11524 Darifenacin Abbreviation: OAB, overactive bladder.

61 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:

62 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

63 Sensory and Pain Symptoms Sensory symptoms – Trigeminal neuralgia (one of the more common symptoms) – Burning, itching, LHermittes sign, face twitching – Carbamazepine 200 mg PO BID or TID – Gabapentin, topiramate, tiagabine, tricyclic 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: Schapiro RT. Ann Indian Acad Neurol. 2009;12: Henze T, et al. Eur Neurol. 2006;56:

64 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

65 ARS Question: In a patient with fatigue and depression, which of the following would be the most appropriate treatment option? 1) Tricyclic antidepressants (TCAs) 2) Fluoxetine (this is correct) 3) Paroxetine 4) Mirtazapine

66 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 (TCAs) 2) Fluoxetine 3) Paroxetine 4) Mirtazapine 25.0% 23.5% 43.8% 18.8%

67 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 (TCAs) 2) Fluoxetine 3) Paroxetine 4) Mirtazapine 9.1% 90.9% 0.0%

68 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)

69 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) Darifenacin 39.3% 7.1% 25.0% 28.6%

70 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% 0.0% 71.4%

71 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

72 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

73 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)

74 Common Issues Facing Patients with Multiple Sclerosis Spasticity Walking/mobility issues Fatigue Sexual dysfunction

75 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

76 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 spasticity 2 1. Henze T. Int MS J. 2007;14: OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

77 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

78 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 85 o F (warmer temperatures cause fatigue; colder temperatures exacerbate spasticity) Mechanical aids –Orthotics –Braces OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Henze T. Int MS J. 2007;14: Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

79 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

80 Spasticity Pharmacologic Treatments Second-line agents; frequently used in combination with oral baclofen –Tizanidine –Diazepam –Clonazepam –Dantrolene –Clonidine Refractory spasticity –Botulinum toxin –Intrathecal baclofen OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Henze T. Int MS J. 2007;14: Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

81 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! OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

82 Walking/Mobility Issues Gait disturbances are a common symptomatic problem Extended Disability Status Scale (EDSS) scoring used to assess walking mobility issues

83 Available at: Kurtzke JF, et al. Neurology. 1983;33: EDSS Scoring

84 Walking/Mobility Issues Traditionally have been managed using nonpharmacologic treatments (ie, exercise, physical therapy, gait training, assistive devices)

85 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.

86 Dalfampridine Pivotal Trials Evaluated in 2 controlled trials involving 540 patients –Study 1: randomized, placebo-controlled, parallel group, 21-week study in 301 patients 1 –Study 2: randomized, placebo-controlled, parallel group, 14-week study in 239 patients 2 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: Goodman AD, et al. Mult Scler. 2008;14:S298. Abstr. P909.

87 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 placebo 3 1. Goodman AD, et al. Lancet. 2009;373: Goodman AD, et al. Mult Scler. 2008;14:S298. Abstr. P Dalfampridine [PI]. Hawthorne, NY: Acorda Therapeutics; 2010.

88 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.

89 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.

90 Dalfampridine vs 4-Aminopyridine Not bioequivalent Cannot be substituted Dalfampridine only indicated for walking/mobility issues

91 Fatigue 60%–97% of patients report fatigue 1,2,3 15%–40% report that it is the worst symptom of their disease 1 Traditionally, fatigue has been evaluated through patient self-reporting questionnaires –Subjective –Can be confounded by other symptoms 1. OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Goldman MD, et al. Cleve Clin J Med. 2006;73: Henze T. Int MS J. 2007;14:22-27.

92 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: Henze T. Int MS J. 2007;14:22-27.

93 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

94 Treating Fatigue Pharmacologic Treatments Modafinil 1-3 –100–400 mg once daily in the AM –First-line agent for improving daytime fatigue 4-aminopyridine 1-3 –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 Amantadine 1-3 –100 mg twice daily (AM and in the early afternoon) 1. Goldman MD, et al. Cleve Clin J Med. 2006;73: OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Henze T. Int MS J. 2007;14:22-27.

95 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 contraception 1 –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:

96 Sexual Dysfunction Common in both males and females 1-3 Affects ~75% of patients 1,3 Can be caused by a variety of factors 2,3 –Depression –Fatigue –Neurologic impairment –Pain –Concurrent medications 1. Henze T. Int MS J. 2007;14: OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

97 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: OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Crayton H, et al. Neurology. 2004;63(11 suppl 5): S

98 Treating Sexual Dysfunction in Males First line –Phosphodiesterase inhibitors (eg, sildenafil) 1-4 Second line –Alprostadil injections –Amantadine –Penile prosthetic devices 1,2 1. OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Goldman MD, et al. Cleve Clin J Med. 2006;73: Henze T. Int MS J. 2007;14: Crayton H, et al. Neurology. 2004;63(11 suppl 5):S12-18.

99 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 OConner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

100 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

101 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

102 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 % 0.0% 4.6% 18.2%

103 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% 93.8%

104 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)

105 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%

106 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%


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