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Robert J. Lipsy, PharmD, BCPS, FASHP

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2 Robert J. Lipsy, PharmD, BCPS, FASHP
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? Reduce the frequency of exacerbations and the progression of CNS disease burden Eliminate exacerbations and the progression of CNS disease burden Reduce the frequency of exacerbations and progression of CNS disease burden and reverse disability due to CNS disease Reduce the intensity and duration of exacerbations According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 3

4 ARS Question: Factors the can negatively affect medication adherence in MS include which of the following? Needle phobia, adverse reactions, and perceived lack of efficacy Needle phobia, adverse reactions, perceived lack of efficacy, and MS-related fatigue Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, and cost Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, cost, and depression According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 4

5 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 According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 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: 5

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

7 Potential Triggers for MS
Potential Triggers for Multiple Sclerosis Several factors are believed to be triggers for MS, but the exact cause is unknown. The reasons for variations in the prevalence and incidence of MS worldwide are not understood (Noseworthy et al 2000). Environmental factors and genetic predisposition have been suggested as possible reasons for these variations (Noseworthy et al 2000). Infection also may play a role in the development of MS (Gilden et al 2005). Several viruses that cause demyelinating encephalomyelitis have been observed in humans. Demyelination can be induced in research animals infected with viruses. An individual in the general population (from northern Europe/northern North America) has a lifetime risk of MS of approximately 0.1%–0.2%1 Risk in an individual with an affected family member is increased, roughly in proportion to the degree of shared genetic information1-5 In an identical twin, the relative risk approaches 200 times that in the general population (~ 25%)1,2,4,5 Multiple genes must be involved in susceptibility Environmental factors must also be involved in disease pathogenesis Gilden DH. Infectious causes of multiple sclerosis. Lancet Neurol. 2005;4: Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 2000;343: Genetic predisposition Environmental factors Infectious agent Abnormal immunologic response 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 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 Pathology of MS Inflammation leads to demyelination, the loss of the myelin sheath, which slows conduction along the nerve axon and leads to neurologic symptoms. When the inflammation decreases, the symptoms abate. However, there is evidence that the nerve axons are damaged due to MS and this damage is associated with permanent neurologic dysfunction.1 MS lesions occur in specific areas of the CNS (eg, the optic nerves, periventricular white matter, brain stem, cerebellum, spinal cord). A patient experiences symptoms related to the location of the lesions within the CNS. When acute inflammation decreases, symptoms remit partially or completely. Reference 1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338: ©2008 Partners Harvard Medical International. Trapp BD, et al. N Engl J Med. 1998;338: Gordon-Lipkin, et al. Neurology. 2007;69:

9 Types of Multiple Sclerosis (MS)
Relapsing-remitting (RRMS) Secondary-progressive (SPMS) Primary-progressive (PPMS) Progressive-relapsing (PRMS) Relapsing-remitting Disability Secondary-progressive Primary-progressive Progressive-relapsing Types of MS MS can follow 1 of 4 disease courses. In the Relapsing-Remitting (RRMS) form of MS (comprising the majority of newly-diagnosed MS patients), unpredictable attacks occur, followed by periods of remission wherein damage may resolve or remain permanent. The majority of RRMS patients will eventually move on to Secondary Progressive MS (SPMS), which is characterized by an initial period of attacks and remissions and then a sudden steady decline of CNS function without periods of remission. The remaining newly-diagnosed MS patients who do not have RRMS are said to have either Primary Progressive MS (PPMS) or Progressive-Relapsing MS (PRMS). The first is characterized by a steady decline from the beginning without remissions and without clear attacks. The second is characterized by a steady decline in CNS function from the onset of MS but also with attacks. Time Graphic courtesy of Dr. Robert J. Lipsy. Lublin FD, Reingold SC. Neurology. 1998;46: 9

10 Untreated Multiple Sclerosis
Silent Phase Relapsing & Remitting Secondary Progressive Early Late Visible Progression and axonal loss Invisible MRI Activity MRI=magnetic resonance imaging Reprinted with permission from the Multiple Sclerosis Foundation

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

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
IM IFNβ-1a SC IFNβ-1a SC IFNβ-1b Glatiramer acetate Fingolimod Natalizumab Mitoxantrone First-line therapies Second-line therapy Worsening/ progressive disease 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 acetate1 (Copaxone®) CIS RRMS 20 mg/d SC Low-dose IFNβ-1a2 (Avonex®) 30 mcg/wk IM High-dose IFNβ-1a3 (Rebif®) CIS† 22 mcg or 44 mcg TIW SC High-dose IFNβ-1b4,5 (Betaseron®, Extavia®) 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 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®). 2. Mitoxantrone (Novantrone®) s030s031lbl.pdf

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

19 Emerging MS Therapies GA Tx-naive IFNb patients First-line therapies
Fingolimod Tx-naive patients 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 Main emerging therapies and strategies Oral agents Cladribine Laquinimod Teriflunomide Fumaric acid Monoclonal antibodies Daclizumab Alemtuzumab Rituximab Ocrelizumab Combination therapy IFNb-based GA-based Novel agents MS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at: Abbreviations: GA, glatiramer acetate; IFNb, interferon beta.

20 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 ) 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 Development—Monoclonal Antibodies
Agent Mechanisms of Action Alemtuzumab Anti-CD52 Depletes T and B lymphocytes Daclizumab Anti-CD25 (IL-2 receptor α-chain) Inhibits T lymphocyte activation and expansion  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 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 Multiple sclerosis is a complicated disease and may not be well-understood among the patient population. Patients suffering from aichmophobia (fear of needles) may not only have difficulty with initiating parenteral therapy but also with continuing therapy if the phobia is never overcome. Patients may encounter barriers in adopting a new daily routine, especially one that involves injections. Additional barriers arise if the patient expects low treatment efficacy. With the introduction of oral therapy to the market, patient adherence to disease-modifying drugs may increase. This less invasive route of administration will eliminate non-adherence stemming from aichmophobia and reluctance to adapt a new daily routine involving injections. Oral medications can also be taken “on-the-go,” allowing for more flexible lifestyles, while parenteral therapy must be administered at home or in a medical facility. In a 1997 study in the Archives of Neurology, 41% of patients reported new or increased depression within 6 months of starting interferon treatment. Patients experiencing symptoms of depression were more likely than others to discontinue treatment. The study’s concluding remarks suggested that treating patient-reported depression may increase adherence to disease-modifying therapy. In a more recent study (2007) in the Journal of Neurological Sciences, it was concluded that the most frequent cause of stopping treatment is the perceived lack of efficacy. The study also determined that most withdrawals from treatment occur during the first year. This information illustrates again the importance of patient education and overall well-being. 1. Mohr DC, et al. Arch Neurol. 1997;54: Clerico M, et al. J Neurol Sci. 2007;259: 22

23 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) 27 Fraser et al (2004) 21.2 Haas & Firzlaff (2005) 2 years 30.2 Turner et al (2007) Portaccio et al (2008) 4 years 45.8 This slide presents summary of the results from empirical studies on adherence to MS DMTs. Major types of nonadherence are (1) complete refusal of therapy, (2) refusal of specific treatment options and (3) arbitrary or unintended modification of prescriptions. 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 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 Multiple sclerosis is a complicated disease and may not be well-understood among the patient population. Patients suffering from aichmophobia (fear of needles) may not only have difficulty with initiating parenteral therapy but also with continuing therapy if the phobia is never overcome. Patients may encounter barriers in adopting a new daily routine, especially one that involves injections. Additional barriers arise if the patient expects low treatment efficacy. With the introduction of oral therapy to the market, patient adherence to disease-modifying drugs may increase. This less invasive route of administration will eliminate non-adherence stemming from aichmophobia and reluctance to adapt a new daily routine involving injections. Oral medications can also be taken “on-the-go,” allowing for more flexible lifestyles, while parenteral therapy must be administered at home or in a medical facility. In a 1997 study in the Archives of Neurology, 41% of patients reported new or increased depression within 6 months of starting interferon treatment. Patients experiencing symptoms of depression were more likely than others to discontinue treatment. The study’s concluding remarks suggested that treating patient-reported depression may increase adherence to disease-modifying therapy. In a more recent study (2007) in the Journal of Neurological Sciences, it was concluded that the most frequent cause of stopping treatment is the perceived lack of efficacy. The study also determined that most withdrawals from treatment occur during the first year. This information illustrates again the importance of patient education and overall well-being. Rio J, et al. 17% (107/632) had stopped IMD More patients with SPMS stopped than RRMS ½ stopped because of lack of efficacy ¼ stopped because of side effects ¼ stopped for reasons unrelated to efficacy or side effects 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: 24 24

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: 25

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: 26

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
High Out-of-Pocket Expenses Associated with Lower Medication Adherence Curkendall et al evaluated the impact of patient out-of-pocket (OOP) expenditures on adherence and persistence with biologic drugs in patients with rheumatoid arthritis. For this study, researchers used an inception cohort of RA patients with pharmacy claims for etanercept or adalimumab during 2002 to 2004 which was selected from an insurance claims database of self-insured employer health plans (n = 2,285) in the US. Researchers defined adherence as medication possession ratio (MPR): proportion of the 365 follow-up days covered by days supply. They determined persistence using a survival analysis of therapy discontinuation during follow-up. Researchers measured patient OOP cost as the patient’s co-insurance and co-payments per week of therapy, and as the proportion of the total medication charges paid by the patient. Multivariate linear regression models of MPR and proportional hazards models of persistence were used to estimate the impact of cost, adjusting for insurance type and demographic and clinical variables. Persistence analyses, which used the same 1-year follow-up period as adherence analyses, showed similar results. Univariate Kaplan-Meier curves illustrated that persistence was markedly better for patients with OOP costs below $50 for weekly therapy compared with those who paid more than $50 for a week of therapy (as illustrated by graph). The probability of persisting for 1 year was 32% for patients with OOP costs above $50/week compared with 57% for patients with OOP costs less than $50/week. The adjusted hazard ratio (hazard ratio 1.579, P < 0.001) indicates that patients with OOP costs greater than $50/week were 58% more likely to stop therapy than those with lower OOP costs. Also, patients were 8% more likely to stop therapy for every $10 increase in weekly OOP costs (hazard ratio 1.008, P < 0.001). An increase of 1 percentage point in the patient’s share of the therapy cost increased the probability of therapy discontinuation by 2.7% (hazard ratio 1.027, P < 0.001). Other variables that led to worse persistence were a higher Charlson score and a previous prescription for a narcotic analgesic 6 months prior to therapy initiation. Persistence was better in older patients. Results: The mean + SD OOP expenditures averaged $ $14.15 per week. Most patients (92%) paid less than $20 OOP for therapy per week. The mean + SD MPR was Adherence significantly decreased with increased weekly OOP (coeff = – , P < ) and with a higher proportion of therapy costs paid by patients (coeff = – , P < ), translating into ~ 1 week of therapy lost per $5.50 increase in weekly OOP. Patients whose weekly cost exceeded $50 were more likely to discontinue than patients with lower costs (hazard ratio 1.58, P < 0.001). The researchers concluded that most patients pay less than $20 per week for biologics, but a small number have high OOP expenses, associated with lower medication compliance. The adverse impact of high OOP costs on adherence, persistence, and outcomes must be considered when making decisions about increasing co-payments. Univariate Kaplan-Meier curves illustrating persistence on anti-TNF therapy for patients with out-of-pocket payments over VERSUS under $50 per week. With permission from Curkendall S, et al. Arthritis Rheum. 2008;59:

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 30

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 Less Common Common Vision problems Headache 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 Multidisciplinary Team Approach
Neurologist Physical Therapist Pharmacist Nurse/APN Primary Care Physician Psychologist/ Neuropsychologist Patient Psychiatrist Social Worker Occupational Therapist Urologist Orthopedist Because the symptoms of MS are so varied and impact many functions, there must be a multidisciplinary team approach to care. Every individual with MS should have a primary care physician as well as a neurologist in the multidisciplinary team overseeing his or her care. Nurses are important members of this team, because patients frequently look to their nurses for information regarding MS. The nurse is the facilitator for independent learning who teaches self-directed learning techniques and empowers the patient to take responsibility for disease management. In addition, the management of primary, secondary, and tertiary symptoms of MS may involve specialists from many areas, such as: Vocational rehabilitation counselors Physical therapists Psychologists/neuropsychologists Occupational therapists Output: Quality of Life, Adherence, Adaptation Speech Pathologist Vocational Counselor Physiatrist 33

34 ARS Question: Disease modifying therapies for multiple sclerosis have been shown to do which of the following? Reduce the frequency of exacerbations and the progression of CNS disease burden Eliminate exacerbations and the progression of CNS disease burden Reduce the frequency of exacerbations and progression of CNS disease burden and reverse disability due to CNS disease Reduce the intensity and duration of exacerbations According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 34

35 Eliminate exacerbations and the progression of CNS disease burden
ARS Question #1 PRE: Disease modifying therapies for multiple sclerosis have been shown to do which of the following? Reduce the frequency of exacerbations and the progression of CNS disease burden Eliminate exacerbations and the progression of CNS disease burden Reduce the frequency of exacerbations and progression of CNS disease burden and reverse disability due to CNS disease Reduce the intensity and duration of exacerbations 80.0% 4.2% According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 0.0% 15.8% 35

36 Eliminate exacerbations and the progression of CNS disease burden
ARS Question #1 POST: Disease modifying therapies for multiple sclerosis have been shown to do which of the following? Reduce the frequency of exacerbations and the progression of CNS disease burden Eliminate exacerbations and the progression of CNS disease burden Reduce the frequency of exacerbations and progression of CNS disease burden and reverse disability due to CNS disease Reduce the intensity and duration of exacerbations 90.0% 0.0% According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 10.0% 0.0% 36

37 ARS Question: Factors the can negatively affect medication adherence in MS include which of the following? Needle phobia, adverse reactions, and perceived lack of efficacy Needle phobia, adverse reactions, perceived lack of efficacy, and MS-related fatigue Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, and cost Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, cost, and depression According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 37

38 Needle phobia, adverse reactions, and perceived lack of efficacy
ARS Question #2 PRE : Factors the can negatively affect medication adherence in MS include which of the following? Needle phobia, adverse reactions, and perceived lack of efficacy Needle phobia, adverse reactions, perceived lack of efficacy, and MS-related fatigue Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, and cost Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, cost, and depression 3.7% 0.0% According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 0.0% 96.3% 38

39 Needle phobia, adverse reactions, and perceived lack of efficacy
ARS Question #2 POST: Factors the can negatively affect medication adherence in MS include which of the following? Needle phobia, adverse reactions, and perceived lack of efficacy Needle phobia, adverse reactions, perceived lack of efficacy, and MS-related fatigue Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, and cost Needle phobia, adverse reactions, perceived lack of efficacy, MS-related fatigue, cost, and depression 0.0% 0.0% According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 0.0% 100.0% 39

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? Tricyclic antidepressants (TCA’s) Fluoxetine (this is correct) Paroxetine Mirtazapine 41

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? Oxybutynin Tolterodine Trospium Darifenacin (this is the correct answer) 42

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 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 Approximately 50% of MS patients suffer from cognitive dysfunction as a result of their illness. Just as the physical symptoms of MS can vary considerably from person to person, cognitive changes can vary as well. Memory impairment ranks as the most commonly experienced cognitive problem. Cognitive rehabilitation is generally the preferred treatment for MS-related cognitive dysfunction. Numerous studies have recently examined pharmacological treatments for MS-related cognitive dysfunction—thus far donepezil hydrochloride appears to be the most effective pharmacological treatment for MS-related cognitive dysfunction. Since cognitive impairments can negatively impact patient compliance, pharmacists should make all attempts to simplify drug regimens to make things easier on patients (e.g., suggest medications that can be given once per day rather than multiple times per day, recommend monotherapy options instead of multi-drug ones). 1.National Multiple Sclerosis Society. 2. O’Conner 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 Depression is very common in chronic diseases, including MS. It has been estimated that up to 50% of all MS patients suffer from depression. While the exact cause of MS-related depression is not fully understood, researchers have hypothesized that it could be a psychological reaction to a chronic illness, part of the grieving process, adverse effect from medications used to treat MS (e.g., interferons), and/or related to the neuropathology of MS. O’Conner 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 Treatments of MS-related depression include both psychotherapy and pharmacotherapy. Multiple sclerosis-related depression typically responds very well to antidepressant medications (e.g., selective serotonin reuptake inhibitors, selective serotonin/norepinephrine reuptake inhibitors, and tricyclic antidepressants). The tricyclic antidepressants or the selective serotonin/norepinephrine reuptake inhibitors should be considered for patients who also suffer from pain and/or insomnia, recognizing that concurrent MS symptoms can cause depression. O’Conner 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 O’Conner 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) O’Conner 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 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 Bladder dysfunction problems include failure to empty, failure to store, or a combination of the two. Failure to empty (detrusor hyperreflexia) is the most common bladder problem seen in MS patients. Patients commonly complain of urinary urgency and frequency and of voiding only small amounts of urine. Over time, urgency can become more difficult to control and can lead to incontinence. Anticholinergic medications (e.g., oxybutynin and tolterodine) are commonly prescribed for failure to store problems. The most common adverse effects associated with these medications include: dry mouth and constipation. Pharmacists should remind patients to increase their fluid intake while taking anticholinergic medications. Although these medications are usually very effective, patients with large postvoid residual volumes (>100 ml) may also need to use intermittent self-catheterization since large urine residual volumes increase the risk of developing urinary tract infections. Failure to store (detrusor sphincter dyssynergia) is a less common bladder dysfunction problem in patients with MS. The condition—which primarily occurs only in men—causes hesitancy, retention, and overflow incontinence. Alpha blocking drugs (e.g., terazosin and tamsulosin) are the drugs of choice for failure to store problems. Pharmacists should tell patients that these products decrease blood pressure and can cause severe dizziness, especially after the first dose. When these drugs are not effective, adjunctive measures (e.g., pads, undergarments, condom catheters) may help to improve the patient’s quality of life by minimizing the embarrassing effects of overflow incontinence. 1. O’Conner 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) Imipramine is a TCA with anticholinergic, alpha-adrenergic, and CNS effects. It can prove helpful on its own or in combination with oxybutynin. Goldman MD, et al. Cleve Clin J Med. 2006;73:

58 Bladder Dysfunction Pharmacologic Treatments
Failure to store (hyperreflexive bladder) Anticholinergic medications (eg, oxybutynin, tolterodine)1,2 With or without low-dose imipramine (synergistic effect) Remove cholinergic agent if incontinence started soon after its initiation Failure to store (sphincter dyssynergia) Alpha blocking drugs (eg, terazosin and tamsulosin, alfuzosin, silodosin) are the drugs of choice for failure to store problems1,2 Relaxes the internal sphincter 1. Goldman MD, et al. Cleve Clin J Med. 2006;73: Schapiro RT. Neurorehabil Neural Repair. 2002;16:

59 Treatment—Urge UI/OAB (Based on Cost/Insurance Coverage)
1st Line Oxybutynin: 2.5–5 mg 2–4 times daily Oxybutynin XL (Ditropan XL®): 5–30 mg daily Oxybutynin gel (Gelnique®): 1 g daily Tolterodine (Detrol®): 1–2 mg twice daily – w/3A4 inhibitor, decrease dose Tolterodine LA (Detrol LA®): 2–4 mg daily 2nd Line Oxybutynin patch (Oxytrol®): 3.9 mg 2x/week Fesoterodine (Toviaz®): 4–8 mg ER daily Trospium (Sanctura®): 20 mg 1–2 times daily – not metabolized Trospium XR (Sanctura XR®): 60 mg daily Solifenacin (Vesicare®): 5–10 mg daily Darifenacin (Enablex®): 7.5–15 mg daily Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name. Abbreviations: OAB, overactive bladder; UI, urinary incontinence.

60 Comparison of OAB Agents
Drug Dry Mouth (%) Constipation Dizziness Vision Changes Oxybutynin 85 40 32 20 Oxy ER/XL 35 7 5 2 Oxy TDS 3 1 Oxy gel 8 ? Tolterodine 61, 23 13, 6 6, 2 8, 1 Fesoterodine 6 Trospium 10 Solifenacin 11 4 Darifenacin 15 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 Anticholinergic medications (e.g., oxybutynin and tolterodine) are commonly prescribed for failure to store problems. The most common adverse effects associated with these medications include: dry mouth and constipation. Pharmacists should remind patients to increase their fluid intake while taking anticholinergic medications. Although these medications are usually very effective, patients with large postvoid residual volumes (>100 ml) may also need to use intermittent self-catheterization since large urine residual volumes increase the risk of developing urinary tract infections. Failure to store (detrusor sphincter dyssynergia) is a less common bladder dysfunction problem in patients with MS. The condition—which primarily occurs only in men—causes hesitancy, retention, and overflow incontinence. Alpha blocking drugs (e.g., terazosin and tamsulosin) are the drugs of choice for failure to store problems. Pharmacists should tell patients that these products decrease blood pressure and can cause severe dizziness, especially after the first dose. When these drugs are not effective, adjunctive measures (e.g., pads, undergarments, condom catheters) may help to improve the patient’s quality of life by minimizing the embarrassing effects of overflow incontinence. O’Conner 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, 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: 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? Tricyclic antidepressants (TCA’s) Fluoxetine (this is correct) Paroxetine Mirtazapine 65

66 Tricyclic antidepressants (TCA’s) Fluoxetine Paroxetine Mirtazapine
ARS Question #1 PRE : In a patient with fatigue and depression, which of the following would be the most appropriate treatment option? Tricyclic antidepressants (TCA’s) Fluoxetine Paroxetine Mirtazapine 18.8% 43.8% 25.0% 23.5% 66

67 Tricyclic antidepressants (TCA’s) Fluoxetine Paroxetine Mirtazapine
ARS Question #1 POST: In a patient with fatigue and depression, which of the following would be the most appropriate treatment option? Tricyclic antidepressants (TCA’s) Fluoxetine Paroxetine Mirtazapine 9.1% 90.9% 0.0% 0.0% 67

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? Oxybutynin Tolterodine Trospium Darifenacin (this is the correct answer) 68

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? Oxybutynin Tolterodine Trospium Darifenacin 28.6% 25.0% 7.1% 39.3% 69

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? Oxybutynin Tolterodine Trospium Darifenacin 14.3% 14.3% 0.0% 71.4% 70

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 Baclofen withdrawal can be very dangerous
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? Baclofen withdrawal can be very dangerous Patients should never just stop taking baclofen without talking to their prescriber The patients hair could fall out because he stopped taking baclofen “cold turkey” 1 and 2 72

73 ARS Question: Which of the following statement about dalfampridine is true?
Dalfampridine is the 1st approved product for MS to help with cognitive impairment Dalfampridine contains the same active ingredient as 4-aminopyridine Dalfampridine and 4-aminopyridine can be interchanged (substituted for each other) 73

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 Spasticity—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:

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 spasticity2 1. Henze T. Int MS J. 2007;14: O’Conner 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 The goal of therapy when treating spasticity is to reduce symptoms in order to improve patient comfort and function—rather than to completely eliminate the spasticity. Interestingly enough, some degree of spasticity actually helps patients with lower-extremity weakness walk because it offers some limb stabilization. Rehabilitation—which is considered the key to managing spasticity—should be tailored to each patient’s degree of impairment and disability. However, rehabilitation rarely alleviates all symptoms. Medications that decrease spasticity are often used as adjuncts to rehabilitation. O’Conner 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 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: 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 Orally-administered baclofen is considered the first-line treatment for spasticity. Because baclofen can cause significant weakness, dosages should be started low (e.g., 5 to 10 mg three times per day) and titrated upward slowly, as needed, to a maximum daily dose of 120 mg/day. Common adverse effects of baclofen include somnolence and confusion. Over time these adverse effects tend to lessen dramatically. When counseling patients about baclofen, remind them to avoid suddenly stopping the drug since abrupt withdrawal can lead to hallucinations, seizures, and death. O’Conner 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 Tizanidine is also frequently used to treat spasms. It appears to be as effective as baclofen in treating spasms but tends to cause significantly less weakness. The starting dose of tizanidine is 2 mg at bedtime. This drug causes extreme sedation; therefore, doses must be gradually increased to a maximum dose of 36 mg/day (given in three to four divided doses each day). Common adverse effects of tizanidine include: sedation, dry mouth, hypotension, and constipation. In severe cases of spasticity, baclofen and tizanidine can be combined. Other products commonly used to treat spasms include: diazepam, clonazepam, dantrolene, and clonidine. The benzodiazepines (diazepam and clonazepam) are most commonly used to treat nocturnal spasms that are refractory to baclofen and tizanidine. Dantrolene is typically reserved for patients who cannot walk and are therefore not affected by the muscle weakness that it causes. It is important to note that all of these products can cause drowsiness. Reassure patients that the drowsiness usually decreases with time. Botulinum toxin (type A or type B) is increasingly being used to treat MS spasticity, especially in patients with focal target areas (e.g., difficulty with self-catheterization and hygiene due to spasticity of the hip adductors). The drug is delivered by intramuscular injection; however, localization with electromyelography or electrical stimulation may be needed to find small or deep muscles. The effects of botulinum toxin occur within a few days to up to 2 weeks after injection, and typically last from 3 to 6 months. Periodic repeat injections are needed to maintain the benefit. Generally speaking, botulinum toxin is usually safe and well tolerated with local muscle weakness and atrophy being the most commonly reported adverse events. Although botulinum toxin is not an approved treatment for spasticity, many insurance companies will pay for its use in patients with MS. Patients who cannot tolerate or who are unresponsive to oral monotherapy or combination therapy with anti-spasm medications usually benefit from intrathecal baclofen. This form of baclofen is markedly more effective and better tolerated than oral baclofen in patients suffering from severe spasms who are wheelchair bound. Intrathecal baclofen is delivered through a surgically implanted catheter and pump. O’Conner 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! O’Conner 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 EDSS Scoring Available at: www.msdecisions.org.uk.
Kurtzke JF, et al. Neurology. 1983;33: 83

84 Walking/Mobility Issues
Traditionally have been managed using nonpharmacologic treatments (ie, exercise, physical therapy, gait training, assistive devices) Acordia Therapeutics recently announced the approval of dalfampridine (Ampyra) for the treatment of gait disturbances in patients with multiple sclerosis (MS). Dalfampridine contains the same active ingredient as 4-aminopyridine (4-AP, fampridine), a medication that patients with MS have been obtaining from compounding pharmacies for over 15 years. Dalfampridine is classified as a potassium channel blocker. Exactly how dalfampridine improves mobility in patients who have MS is not known. It has been proposed that dalfampridine improves conduction in nerve fibers in which myelin has been damaged, thus improving mobility.

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 Acordia Therapeutics recently announced the approval of dalfampridine (Ampyra) for the treatment of gait disturbances in patients with multiple sclerosis (MS). Dalfampridine contains the same active ingredient as 4-aminopyridine (4-AP, fampridine), a medication that patients with MS have been obtaining from compounding pharmacies for over 15 years. Dalfampridine is classified as a potassium channel blocker. Exactly how dalfampridine improves mobility in patients who have MS 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 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 The efficacy of safety of dalfampridine in improving walking in patients with MS was evaluated in two controlled trials involving 540 patients. The first study was a randomized, placebo-controlled, parallel group, 21 week study in 301 patients; and the second study was a randomized, placebo-controlled, parallel group, 14 week study in 239 patients. The primary efficacy measure in the two studies was walking speed as measured by the Timed 25-foot walk (T25W). In both studies, fampridine-treated patients had significantly improved walking speeds (Trial 1: 34.8% vs. 8.3% [p<0.0001], Trial 2: 42.9% vs. 9.3% [p<0.001]). In addition, a significantly greater proportion of patients taking fampridine had increased walking speed of at least 10%, 20%, or 30% from baseline, compared to placebo. 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 placebo3 The efficacy of safety of dalfampridine in improving walking in patients with MS was evaluated in two controlled trials involving 540 patients. The first study was a randomized, placebo-controlled, parallel group, 21 week study in 301 patients; and the second study was a randomized, placebo-controlled, parallel group, 14 week study in 239 patients. The primary efficacy measure in the two studies was walking speed as measured by the Timed 25-foot walk (T25W). In both studies, fampridine-treated patients had significantly improved walking speeds (Trial 1: 34.8% vs. 8.3% [p<0.0001], Trial 2: 42.9% vs. 9.3% [p<0.001]). In addition, a significantly greater proportion of patients taking fampridine had increased walking speed of at least 10%, 20%, or 30% from baseline, compared to placebo. 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) Patient counseling: Instruct patients to take dalfampridine exactly as prescribed and tell them to never double doses. The first dose of dalfampridine 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 of dalfampridine as soon as possible unless it is almost time for the next dose. Dalfampridine can be taken with or without food. If gastrointestinal upset occurs, suggest that dalfampridine be taken with food. Dalfampridine 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.

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 Patient counseling: Instruct patients to take dalfampridine exactly as prescribed and tell them to never double doses. The first dose of dalfampridine 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 of dalfampridine as soon as possible unless it is almost time for the next dose. Dalfampridine can be taken with or without food. If gastrointestinal upset occurs, suggest that dalfampridine be taken with food. Dalfampridine 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 What is Fampridine SR used to treat? Initially, Fampridine SR will only be approved to treat people with MS who suffer from gait disturbances. However, it is also being studied as a treatment of fatigue and heat sensitivity in patients with MS. Likewise, it is also being studies as a treatment for gait disturbances in people who have suffered a spinal cord injury. Is Fampridine SR the same a 4-Aminopyridine? Fampridine SR contains the same active ingredient as 4-aminopyridine (or 4AP), a medication that MS patients have been purchasing from compounding pharmacies for many years. Fampridine SR differs from 4-aminopyridine in how it is released in the body. Because Fampridine SR is a sustained-release product (hence the SR in the name) it has an increased duration of effect and does not have to be dosed as often as compounded 4-aminopyridine. How should Fampridine SR be taken? It is very important to take Fampridine SR exactly as directed by your doctor. Most people will be prescribed the medication twice per day. The first dose should be taken first thing in the morning and the second dose should be taken in the early afternoon. IF you forget to take a dose, take the missed dose as soon as possible unless it is almost time for the next dose. Never take two doses at the same time. Fampridine SR can be taken with or without food. It is very important to swallow the capsule whole. IT SHOULD NEVER BE CRUSHED OR CHEWED! Are there any special instructions regarding taking Fampridine SR? This product should not be taken by women who are pregnant, nursing, or trying to get pregnant; or in people who have epilepsy or who have kidney problems. What are the common adverse effects associated with Fampridine SR? Drowsiness, light headedness, and dizziness are very common; therefore, patients should careful driving a car or using dangerous machinery Numbness and tingling in the face or hands Stomach problems (nausea, vomiting, constipation, or abdominal pain) can occur; when stomach problems occur try taking the medicine with food or milk Restlessness Anxiety Headache When should I call my doctor? It Fampridine SR causes severe confusion or agitation, you should notify your doctor. If you have a seizure while taking Fampridine SR, you should STOP taking the medicine and also notify your doctor ASAP.

91 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 Fatigue—one of the most common complaints of MS patients—often limits activities of daily living, job performance, and quality of life. Approximately 90% of MS patients experience fatigue. 1. O’Conner 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 Although MS-related fatigue is a common problem, clinicians should evaluate patients for coexisting medical conditions (e.g., thyroid disease, anemia, sleep disturbances) that could cause or contribute to fatigue. The degree of MS-related fatigue varies from patient to patient. While the exact cause of MS-related fatigue is not clear, it is known that MS-related fatigue worsens before and during exacerbations and with external and core temperature increases. Not surprisingly, spasticity and weakness can also worsen MS-related fatigue. 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 O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006:

94 Treating Fatigue Pharmacologic 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) Multiple sclerosis-related fatigue is best treated with a combination of low-impact aerobic exercise and anti-fatigue medications. First-line agents used to treat fatigue include: amantadine or modafinil. Since modafinil can reduce the efficacy of hormonal contraception remind women of childbearing age who use oral contraceptives, to use a back-up form or alternative form of contraception. Other agents used to treat MS-related fatigue include: methylphenidate (RARELY USED), fluoxetine, and 4-aminopyridine. 1. Goldman MD, et al. Cleve Clin J Med. 2006;73: O’Conner 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 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:

96 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: O’Conner 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: O’Conner P. In: Multiple Sclerosis and Demyelinating Diseases. Lippincott, Williams, and Wilkins; 2006: Crayton H, et al. Neurology. 2004;63(11 suppl 5): S12-18.

98 Treating Sexual Dysfunction in Males
First line Phosphodiesterase inhibitors (eg, sildenafil)1-4 Second line Alprostadil injections Amantadine Penile prosthetic devices1,2 In men, sexual dysfunction can typically be treated successfully with drugs such as Viagra and alprostadil. Viagra is considered the “gold standard” for sexual dysfunction in men. When Viagra fails or is not effective enough, alprostadil injections are an option. While not as common as Viagra or alprostadil, amantadine can be used for sexual dysfunction. Amantadine is much cheaper than Viagra or alprostadil. The penile prosthetic devices were very popular before the days of Viagra. These devices are not used that much anymore. 1. O’Conner 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 O’Conner 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 Baclofen withdrawal can be very dangerous
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? Baclofen withdrawal can be very dangerous Patients should never just stop taking baclofen without talking to their prescriber The patients hair could fall out because he stopped taking baclofen “cold turkey” 1 and 2 101

102 Baclofen withdrawal can be very dangerous
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? Baclofen withdrawal can be very dangerous Patients should never just stop taking baclofen without talking to their prescriber The patients hair could fall out because he stopped taking baclofen “cold turkey” 1 and 2 0.0% 4.6% 18.2% 77.3% 102

103 Baclofen withdrawal can be very dangerous
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? Baclofen withdrawal can be very dangerous Patients should never just stop taking baclofen without talking to their prescriber The patients hair could fall out because he stopped taking baclofen “cold turkey” 1 and 2 6.3% 0.0% 0.0% 93.8% 103

104 ARS Question: Which of the following statement about dalfampridine is true?
Dalfampridine is the 1st approved product for MS to help with cognitive impairment Dalfampridine contains the same active ingredient as 4-aminopyridine Dalfampridine and 4-aminopyridine can be interchanged (substituted for each other) 104

105 Dalfampridine contains the same active ingredient as 4- aminopyridine
ARS Question #2 PRE : Which of the following statement about dalfampridine is true? Dalfampridine is the 1st approved product for MS to help with cognitive impairment Dalfampridine contains the same active ingredient as 4- aminopyridine Dalfampridine and 4-aminopyridine can be interchanged (substituted for each other) 31.8% 50.0% 18.2% 105

106 Dalfampridine contains the same active ingredient as 4- aminopyridine
ARS Question #2 POST: Which of the following statement about dalfampridine is true? Dalfampridine is the 1st approved product for MS to help with cognitive impairment Dalfampridine contains the same active ingredient as 4- aminopyridine Dalfampridine and 4-aminopyridine can be interchanged (substituted for each other) 14.3% 81.0% 4.7% 106


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