Current and emerging therapies in the management of multiple sclerosis

Transcription

1 Reviews Current and emerging therapies in the management of multiple sclerosis American Pharmacists Association Overview of multiple sclerosis Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). 1 MS causes a variety of symptoms that can affect functional ability and quality of life considerably. Affecting approximately 400,000 people in the United States, with 200 new cases diagnosed weekly, 2 MS is the leading cause of nontraumatic neurologic disability in young adults. 3 MS typically presents between age 20 and 50 years, is two to three times more common in women than men, 2 and is nearly two times more common in whites than blacks. 3 Pathogenesis MS is characterized by destruction of the myelin on neurons (demyelination) and subsequent damage to the underlying axon (Figure 1). Activated T-cells and other immune cells cross the blood brain barrier into the CNS and attack the myelin sheath on the axons. 4 Resulting inflammation deteriorates the myelin, which slows or interrupts the conduction of nerve impulses along the axons. 5 When acute inflammation decreases, symptoms abate partially or completely. However, demyelination can leave the underlying axon exposed and susceptible to damage. Axon loss is believed to be the major cause of permanent disability in MS. 3 Etiology The exact cause of MS is unknown, although its proposed etiologies may include a combination of several factors such as genetic predisposition (i.e., upregulated immune system) and environmental factors (e.g., previous viral infections). Behavioral factors that also may increase susceptibility to MS include smoking 6 and excess body weight. 7 More research is needed to better understand the importance of these factors in development and progression of MS. Advisory board: Jacquelyn Bainbridge, PharmD, FCCP, Professor, Department of Clinical Pharmacy and Neurology, University of Colorado, Aurora. Ellen Whipple Guthrie, PharmD, Medical Advisory Board, MS Foundation, Ft. Lauderdale, FL; and Clinical Assistant Professor, University of Georgia, Athens. This publication was prepared by Lauren Cerruto and Amanda Bach of MedPen, Inc., on behalf of the American Pharmacists Association. Funding: This activity is supported by independent educational grants from Bayer HealthCare Pharmaceuticals Inc., Biogen Idec, Pfizer Inc., and Teva Pharmaceuticals. Acknowledgement: Any potential faculty conflicts of interest were resolved via peer review by Melody Ryan, PharmD, MPH, University of Kentucky. This article is based on the educational session, Current and Emerging Therapies in the Management of Multiple Sclerosis, presented by Jacquelyn Bainbridge, PharmD, FCCP, and Ellen Whipple Guthrie, PharmD, at APhA2011, the American Pharmacists Association Annual Meeting & Exposition. Accreditation Information Provider: American Pharmacists Association Target audience: Pharmacists ACPE number: H01-P Release date: June 15, 2011 CPE credit: 2.0 hours (0.2 CEUs) Expiration date: June 15, 2014 Learning level: 2 Fee: There is no fee associated with this activity. The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned to this activity by the accredited provider is H01-P. Disclosure: Dr. Bainbridge is a member of an advisory board for Teva Neurosciences, a member of a speaker s bureau for UCB Pharma, and has received grant funding from the National Institutes of Health. Dr. Guthrie has stock in Teva Pharmaceutical Industries Ltd. APhA s editorial staff declare no conflicts of interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see the Education and Accreditation Information section at com/education. Learning objectives At the conclusion of this knowledge-based activity, the pharmacist will be able to: n Describe advances in the understanding of the pathophysiology, etiology, diagnosis, clinical presentation, and disease course of multiple sclerosis (MS). n Review the current clinical management of MS including long-term efficacy and safety of disease-modifying therapies. n Discuss new and emerging therapies for MS. n Describe opportunities for the pharmacist to advance patient care of MS through adherence, managing adverse events, collaborating with health care providers in therapeutic selection, and assisting patients with medication administration. june 2011 Pharmacy Today 63

2 reviews managing multiple sclerosis Figure 1. Demyelination and axonal damage normal axon demyelination axonal damage Created by and used with permission of the National Multiple Sclerosis Foundation. Pretest 1. Conduction of nerve impulses is impaired in multiple sclerosis (MS) as a result of: a. Destruction of myelin and the underlying axon. b. Depletion of dopamine and serotonin. c. Damage to sodium/potassium pumps. d. Dysfunctional receptors on dendrites. 2. After long-term (>15 years) treatment of relapsing-remitting MS with glatiramer acetate: a. Efficacy generally wears off. b. A majority of patients progress to secondary-progressive MS. c. More than 80% continue to walk without assistive devices. d. More than three-quarters of patients show progression on the expanded disability severity scale. 3. A recommended strategy to ameliorate the flulike symptoms of interferon (IFN) is to: a. Stop IFN for 3 months ( drug holiday ). b. Take analgesics at the time of injection or within an hour. c. Administer IFN cold, right from the refrigerator. d. Permanently cut the IFN dose by one-half. Clinical subtypes of MS MS may be categorized into the following four subtypes: Relapsing-remitting MS (RRMS): RRMS is the most common initial phase, occurring in approximately 85% of patients at diagnosis. 5 It is characterized by acute episodes of neurologic decline, called attacks, followed by full or partial recovery with little or no disease progression. This phase can last for years or decades. 5 Secondary-progressive MS (SPMS): Many patients with RRMS transition to SPMS, which is characterized by slow and steady irreversible neurologic dysfunction that occurs with or without attacks. 5 Primary-progressive MS (PPMS): Approximately 10% of patients are initially diagnosed with PPMS, which is characterized by continuous neurologic decline from disease onset without distinct attacks. 5 Progressive-relapsing MS (PRMS): PRMS is rare, occurring in 5% of patients. PRMS is similar to PPMS in that neurologic decline is steady from disease onset; however, occasional distinct attacks may occur. 5 In addition, it is widely recognized that some MS patients have a mild disease course with little to no accumulation of disability over time ( benign MS ); however, little consensus exists regarding how to identify such patients in the early years after diagnosis. 8 Initial presentation of MS The first symptomatic attack consistent with MS is known as clinically isolated syndrome (CIS). CIS can present as a single symptom, such as optic neuritis (inflammation of the optic nerve), or multiple symptoms depending on the number and location of CNS lesions. Approximately 60% to 80% of patients with CIS who have demyelinating lesions on magnetic resonance imaging (MRI) are ultimately diagnosed with clinically definite MS (CDMS). Of important note, 20% of patients with CIS who have normal MRI scans also develop CDMS. 1 Diagnosis of CIS is important so that treatment can be started to delay progression to CDMS. 64 Pharmacy Today june

3 managing multiple sclerosis reviews Assess your knowledge Take a moment to assess your current knowledge by reviewing the case study and answering the following questions. The case study is continued below, and answers to case study questions appear later in the article. T.G., a 17-year-old white girl who lives in Boston, presents with blurred vision in her right eye. MRI is normal. Family history is noteworthy for an aunt who has MS. After further evaluation, T.G. is diagnosed with optic neuritis and CIS. 1. Why was she given a diagnosis of CIS rather than MS? 2. Should this patient receive a disease-modifying therapy at this time, and if so, which one would you recommend? Because first symptoms of MS (Table 1 3 ) are often mild and self-limiting, many patients may not understand why treatment is necessary. Pharmacists can play an active role in educating patients about the importance of early initiation of treatment with disease-modifying therapies (DMTs). Diagnosis of MS The McDonald criteria, the standard for diagnosing MS, requires dissemination of lesions in both space and time, demonstrated through the use of clinical and MRI findings. 9 Dissemination in space can be established with at least two T2 lesions in separate areas of the CNS on MRI, and dissemination in time can be demonstrated with a new T2 or gadolinium-enhancing lesion on follow-up MRI at any time after baseline MRI. However, if MRI at the time of a first attack shows asymptomatic gadolinium-enhancing and nonenhancing lesions simultaneously, dissemination in time can be based on this finding alone, without a follow-up MRI. 9 Current agents for management of MS Seven DMTs are approved by FDA for treatment of RRMS: subcutaneous and intramuscular interferon (IFN)β-1a, subcutaneous IFNβ-1b (available in two brands of the same formulation), glatiramer acetate, fingolimod, and natalizumab. IFNβ and glatiramer acetate have long been used as first-line DMTs. Fingolimod, the first oral MS DMT, may be considered first or second line for relapsing patients, taking into consideration its efficacy, safety data, and clinical presentation of the patient. Natalizumab should be reserved for second-line use, in accordance with its labeling. 10 Mitoxantrone, an antineoplastic agent, is approved for the treatment of SPMS, PRMS, or worsening RRMS 11 but is used infrequently because of safety concerns. IFNβ IFNβ has antiviral, antiproliferative, and immunomodulatory activity Available IFNβ formulations include IFNβ-1a 30 µg i.m. once weekly, IFNβ-1a 22 or 44 µg s.c. three times weekly, and IFNβ-1b 250 µg s.c. every other day. All IFNβ agents are indicated for treatment of RRMS to reduce the frequency of relapse and, with the exception of subcutaneous IFNβ-1a, also are approved for treatment of CIS Pivotal trials of all IFNβ DMTs in RRMS have demonstrated clinical efficacy in lowering relapse rates, reducing number of lesions, and reducing disease burden on MRI. In addition, Table 1. Common presenting symptoms of multiple sclerosis Ataxia (loss of control of body movements) Bladder/bowel dysfunction Depression Fatigue Impaired balance/coordination Incomplete transverse myelitis (caused by spinal cord inflammation Lhermitte symptom (electrical sensation down the spine on neck flexion) Loss of vibration perception Optic neuritis/visual impairment Paresthesias Sexual dysfunction Weakness Source: Reference 3. these drugs delay the progression of physical disability, which is measured by the Krutzke expanded disability severity scale (EDSS). The EDSS scoring system is used primarily in clinical trials to assess extent of physical disability on a scale from 0 (normal neurologic examination) to 10 (death caused by MS). 16 Table 2 summarizes important data from these trials Long-term efficacy of IFNβ DMTs. The 2-year PRISMS (Prevention of Relapses and disability by Interferon β-1a Subcutaneously in Multiple Sclerosis; described in Table 2) continued for another 4 years, with placebo patients randomized to active treatment. Continuing clinical and MRI benefits were noted in both ongoing treatment groups, and the crossover group experienced reductions in relapse count, MRI activity, and lesion burden accumulation compared with their previous placebo period (P < for both doses). 21 These benefits of subcutaneous IFNβ-1a have been sustained for 8 years of follow-up, with the original 44-µg-three-times-weekly treatment group showing lower relapse rates, disease progression, and accumulated disease burden than the crossover group. 22 Reinforcing these long-term findings, a recent post hoc evaluation noted that patients with the highest cumulative dose and the longest cumulative time on treatment (i.e., high exposure) had better clinical outcomes compared with patients who had lower cumulative dose and time on treatment (i.e., low exposure). 23 Long-term (15-year) follow-up of intramuscular IFNβ- 1a also showed durable benefits with regard to slowed progression of disability, overall health, and independence. 24 At 16-year follow-up of the IFNβ-1b study participants, mortality was decreased in the treatment group versus placebo; however, data were missing for a sizable proportion of the original participants. 25 Comparative trials of IFNβ DMTs. Several studies have demonstrated that subcutaneous IFNβ-1a and IFNβ-1b are more effective than intramuscular IFNβ-1a but may have more adverse effects. A randomized investigator-blinded trial compared two IFNβ-1a formulations: IFNβ-1a 44 µg s.c. three times weekly and IFNβ-1a 30 µg i.m. once weekly. 26 At june 2011 Pharmacy Today 65

4 reviews managing multiple sclerosis Table 2. Pivotal trials of IFNβ DMTs IFNβ product Trial, duration (vs. placebo) Study population Primary endpoints Outcomes IFNβ Multiple Sclerosis Study Group, 2 years PRISMS, 2 years MSCRG study, 2 years IFNβ-1b 50 or 250 µg s.c. every other day IFNβ-1a 22 or 44 µg s.c. t.i.w. IFNβ-1a 30 µg i.m. once weekly 372 RRMS patients Differences in RR, proportion of relapse-free patients Reduced RR with 50 µg (1.17, P = ) and 250 µg (0.84, P = ) vs. placebo (1.27); more patients relapse-free with 250 µg (36 vs. 18, P = 0.007). Follow-up MRI analysis showed fewer active and new lesions (median 80% reduction in disease activity vs. placebo, P = ); burden of disease reduced vs. placebo (P = 0.001). 560 RRMS patients Differences in RR Reduced RR with 22 µg (1.82) and 44 µg (1.73) vs. placebo (2.56; P = 0.005); decreased accumulation of physical disability, number of active lesions on MRI. 301 RRMS patients Time to sustained disability progression of 1.0 point on EDSS Significant reductions in primary end point vs. placebo (P = 0.02); 34.9% of control patients and 21.9% of IFNβ-1a group progressed. IFNβ-1a also reduced relapses (P = 0.03) and number/volume of gadolinium-enhancing lesions on MRI (P = ). Abbreviations used: IFN, interferon; MRI, magnetic resonance imaging; MSCRG, Multiple Sclerosis Collaborative Research Group; PRISMS, Prevention of Relapses and disability by Interferon β-1a Subcutaneously in Multiple Sclerosis; RR, relapse rate; RRMS, relapsing-remitting multiple sclerosis. Source: References weeks, more patients were relapse free with IFNβ-1a 44 µg s.c. (75% vs. 63%) and fewer active lesions were observed on MRI with the subcutaneous regimen (P < at 24 and 48 weeks). However, the subcutaneous IFNβ-1a regimen was associated with a higher incidence of injection site reactions (83% vs. 28%), neutralizing antibodies (25% vs. 2%), liver enzyme abnormalities (18% vs. 9%), and modified leukocyte counts (11% vs. 5%). 26 Efficacy of IFNβ-1b compared with low-dose intramuscular IFNβ-1a was demonstrated in a randomized, open-label, prospective study comparing IFNβ-1b 250 µg s.c. every 48 hours with IFNβ-1a 30 µg i.m. once weekly in 188 patients with RRMS. 27 At 2 years, more patients in the IFNβ-1b group were relapse free (51% vs. 36%, P = 0.03) and had no new T2 lesions on MRI (55% vs. 26%, P < ). Neutralizing antibodies and injection site reactions were more frequent in the IFNβ-1b group. 27 In a double-blind dose-comparison study, 802 patients with RRMS were randomized to IFNβ-1a 30 µg i.m. (n = 402) or IFNβ-1a 60 µg i.m. (n = 400) weekly for 36 months or more. 28 No differences were found in clinical or MRI outcomes or rate of 66 Pharmacy Today june 2011 EDSS disability progression between the two groups. No dose effects on relapse rates, number of new or enlarging lesions, or immunogenicity were observed. Incidences of neutralizing antibodies, flulike symptoms, and muscle weakness were slightly higher in the 60-µg group. 28 Together, these studies suggest that efficacy is greater with IFNβ DMTs that are administered more frequently. Adverse effects of IFNβ DMTs. Common adverse effects of IFNβ products are flulike symptoms (e.g., low-grade fever, chills, myalgias) and injection site reactions (e.g., redness, irritation, rarely necrosis). 3 Injection site reactions improve in most patients in 3 to 6 months. 3 Prophylaxis with acetaminophen or a nonsteroidal anti-inflammatory drug can manage flulike symptoms. Slow initiation of the drug, starting with 25% to 50% of the dose and working up weekly to the full dose, also may reduce flulike symptoms. 3,29 Glatiramer acetate Several different mechanisms have been proposed for the therapeutic effect of glatiramer acetate in MS, including activation of regulatory T-cells that suppress other immune cells

5 managing multiple sclerosis reviews involved in demyelination and depletion of T-cells that damage myelin. 30,31 Glatiramer acetate is indicated for patients with RRMS to reduce the frequency of relapses and for patients with CIS. 31 It is administered once daily as a 20-mg subcutaneous injection. Glatiramer acetate has demonstrated short- and long-term efficacy in a prospective study of RRMS. After 2 years of treatment, the annualized relapse rate was reduced by 29% in patients receiving glatiramer acetate (n = 125) compared with placebo (n = 126, P = 0.007). 32 Disability progression was reduced in significantly more patients receiving glatiramer acetate (24.8%) than placebo (15.2%, P = 0.037), as measured by EDSS change since baseline. 30 Treatment was well tolerated. A recent follow-up report after 15 years of treatment noted that in two-thirds of patients with a mean disease duration of 22 years who have continued taking glatiramer acetate (n = 100), 65% had not progressed to SPMS, 57% experienced stabilized or improved EDSS scores, and 82% retained their ambulatory independence without assistive devices. 33 The study is planned to continue for 20 years of follow-up. Recent randomized comparative studies have not found differences in efficacy between glatiramer acetate and higherdose subcutaneous IFNβ formulations. In two trials comparing glatiramer acetate with subcutaneous IFNβ-1b for 2 to 3.5 years, no differences were seen between groups in primary outcomes of lesion volume and relapse risk Both studies also noted no differences between groups in secondary outcomes, including EDSS progression and cognition Similarly, a 2-year comparative trial of glatiramer acetate with subcutaneous IFNβ-1a found no significant differences between groups in time to first relapse, relapse rate, and number or volume of active lesions. 37 Adverse effects of glatiramer acetate. The most common adverse effect of glatiramer acetate is an injection site reaction that can include redness, swelling, and hives or welts. 38 For many patients, this reaction occurs with every injection, especially during the first 3 to 6 months. A rare self-limited (15 20 minutes) postinjection reaction has been associated with glatiramer acetate use, consisting of flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and/or urticaria. 3,31 Patients should be advised that this reaction is temporary and should resolve quickly. They should remain calm, sit with the head upright, and breathe slowly. If symptoms do not abate within a few minutes or they experience swelling in the face, tongue, or eyes or cannot swallow easily, they should call 911. When the reaction does resolve, patients should contact their health care provider and discontinue medication until advised by their health care provider. 38 Lipoatrophy at the injection site also is rare but noteworthy because it has no known treatment and is believed to be permanent. 31 Proper injection technique and daily rotation of injection sites may minimize its occurrence. 31 Fingolimod Fingolimod, the first oral DMT for RRMS, reduces the number of lymphocytes in the circulatory system by preventing their exit from secondary lymph organs and, consequently, their entry into the CNS. 39 Fingolimod is approved for treatment of RRMS to reduce frequency of relapses and delay physical disability. The recommended dose is 0.5 mg orally once daily, to be taken with or without food. 40 In a double-blind, placebo-controlled, Phase III study, 1,272 patients with RRMS were randomized to fingolimod 0.5 or 1.25 mg/day or placebo for 2 years. 41 Compared with placebo, fingolimod 0.5 and 1.25 mg significantly reduced the annualized relapse rate by 54% and 60%, respectively (P < 0.001). Risk of disability progression was reduced in both active treatment groups, as were the number of new or enlarged lesions and loss of brain volume compared with placebo (P < 0.001). 41 A similar placebo-controlled randomized study of fingolimod in RRMS is ongoing. 42 A double-blind, double-dummy, Phase III trial compared fingolimod 0.5 and 1.25 mg/day with IFNβ-1a 30 µg i.m. once weekly for 1 year in 1,292 patients with RRMS. 39 The annualized relapse rate was lower with both doses of fingolimod than with IFNβ-1a (0.16 and 0.20 vs. 0.33, respectively; P < 0.001), and more patients taking fingolimod remained relapse free (83% and 80% vs. 69%, respectively; P < 0.001). Lesion activity and loss of brain volume also were more effectively reduced with both fingolimod doses compared with IFNβ-1a. Disability progression was similar but small among all treatment groups. Adverse effects of fingolimod. Common adverse effects of fingolimod include headache, influenza, diarrhea, back pain, liver enzyme elevations, and cough. 40 Potentially serious adverse effects of fingolimod are malignancies, bradycardia/atrioventricular block (at the first dose only), increased risk of infections, macular edema, and shortness of breath. 40 A risk evaluation and mitigation strategy (REMS) was developed to ensure that health care providers and patients are appropriately advised about the safe use and serious risks of fingolimod. 43 As described in the REMS, patients starting fingolimod should be monitored for bradycardia for at least 6 hours after taking the first dose. 43 Patients may have mild to moderate symptoms of dizziness or fatigue or be aware of a slow or irregular heartbeat that should resolve within 24 hours. Bradycardia typically resolves within 1 month of treatment initiation. 40 Patients should be instructed to contact their health care provider if they experience dizziness, tiredness, or slow or irregular heartbeat at any time during treatment. If treatment is interrupted for 2 weeks or more, monitoring for at least 6 hours is again required after the next dose. Natalizumab Natalizumab is a monoclonal antibody that targets the cellular adhesion molecule alpha-4 integrin, thereby preventing the adhesion of endothelial cells with immune cells, which effectively stops immune cells from entering the CNS. 44 Despite the efficacy of natalizumab, safety concerns have relegated its use to second-line therapy to reduce relapse frequency and delay physical disability in patients with RRMS who have had inadequate response to or cannot tolerate first-line DMTs. It is administered as a 300-mg intravenous infusion once every 4 weeks. Two Phase III trials have demonstrated the efficacy of natalizumab in RRMS. In a double-blind placebo-controlled trial, june 2011 Pharmacy Today 67

6 reviews managing multiple sclerosis Table 3. Early treatment of CIS reduces risk of CDMS Trial, duration DMT (vs. placebo) DMT dose Reduced CDMS risk with DMT Time to conversion (days) PreCISE, 3 years a Glatiramer acetate 20 mg/day s.c 45% (P < 0.001) 722 vs. 336 CHAMPS, 3 years a IFNβ-1a 30 µg/week i.m. 44% (P = 0.002) NR ETOMS, 2 years IFNβ-1a 22 µg/week s.c. 39% (P = 0.047) 569 vs. 252 REFLEX, 2 years b IFNβ-1a c 44 µg s.c. t.i.w. 51% (P < ) NR BENEFIT, 2 years IFNβ-1b 250 µg q.a.d. 50% (P < 0.001) 618 vs. 255 Extension trials DMT DMT dose Reduced CDMS risk with early vs. delayed DMT CHAMPIONS, +2 years IFNβ-1a 30 µg/week i.m. 43% (P = 0.030) NR BENEFIT, +3 years IFNβ-1b 250 µg s.c. q.a.d. 37% (P = 0.003) NR Abbreviations used: BENEFIT, Betaseron (IFNβ-1b) in Newly Emerging MS for Initial Treatment; CDMS, clinically definite multiple sclerosis; CHAMPIONS, Controlled High-risk subjects (IFNβ-1a) Avonex Multiple sclerosis Prevention Study in Ongoing Neurologic Surveillance; CHAMPS, Controlled High-risk subjects (IFNβ-1a) Avonex Multiple sclerosis Prevention Study; DMT, disease-modifying therapy; ETOMS, Early Treatment Of MS study (Rebif); NR, not recorded; PreCISe, Study to Evaluate the Effect of Early Glatiramer Acetate (Copaxone) Treatment in Delaying the Conversion to CDMS of Subjects Presenting with a CIS; REFLEX, REbif FLEXible dosing in early multiple sclerosis. a Placebo arms stopped early to offer all patients open-label treatment with active drug. b Extension trial (REFLEXION) currently ongoing to provide long-term (up to 5 years) follow-up data. c A serum-free formulation of IFNβ-1b was used in this study and is currently not available in the United States. Source: References Pharmacy Today june patients randomized to natalizumab experienced reduced rate of relapse (68%), decreased risk of sustained disability progression (42%), fewer new or enlarging T2 lesions (83%), and fewer gadolinium-enhancing lesions (92%), all of which were significant (P < 0.001) compared with patients on placebo (n = 315). 45 In a randomized, double-blind, Phase III trial, 1,171 patients taking intramuscular IFNβ-1a who had continued to experience disease activity were randomized to intramuscular IFNβ-1a plus placebo (n = 582) or intramuscular IFNβ-1a plus natalizumab (n = 589) for 2 years. 46 Combination therapy resulted in a lower annualized relapse rate (0.34 vs. 0.75, P < 0.001), greater proportion of relapse-free patients (54% vs. 32%, P < 0.001), lower probability of disability progression (23% vs. 29%, P = 0.02), and fewer new or enlarging T2 lesions (0.9 vs. 5.4, P < 0.001). 46 Although effective, combination regimens are not recommended because of increased safety issues. Adverse effects of natalizumab. Common adverse effects associated with natalizumab that lessen over time and do not usually require treatment are headache, fatigue, depression, pain in joints or extremities, abdominal discomfort, and diarrhea. Risk of lower respiratory tract infection, urinary tract infection, gastroenteritis, and vaginitis is increased with natalizumab; patients should be advised to seek prompt medical attention for these conditions. 47 Of particular concern is the risk of progressive multifocal leukoencephalopathy (PML). This rare but serious, untreatable, and often fatal disease increases in risk with continued exposure, especially after 2 years of treatment. 10 PML resulting from MS treatment occurs after a median of 30 infusions. 48 Three cases of PML were reported in clinical trials of natalizumab. 45,46 As of March 2011, 102 confirmed cases of PML had occurred in patients treated with natalizumab since Because of the risk of PML, use of natalizumab in the United States is monitored by the Tysabri Outreach: Unified Commitment to Health system, known as the TOUCH Prescribing Program. This restricted distribution program serves to educate health care providers and patients about use and risks of natalizumab and mandates that 10,49 : Natalizumab is used only as monotherapy in patients with RRMS who have not responded adequately to or who cannot tolerate first-line DMTs. Natalizumab is administered only through infusion centers registered with TOUCH. Before initiating therapy, patients must receive MRI scans. Patients must be evaluated at 3 and 6 months after the first infusion and every 6 months thereafter. Switching therapies Patients who do not respond well to one DMT may need to switch to another first- or second-line DMT. Possible markers of nonresponse to treatment include continued, frequent relapses or MRI findings that show high gadolinium-enhancing activity or considerable new lesion formation not associated with relapse. 50 Switching therapies also may be necessary for patients experiencing intolerable adverse events; however, switching within 6 months of treatment is discouraged because many adverse events lessen over time. 27 Switching from one IFNβ to another also is not advised because IFNβ products have the same mechanism of action and similar adverse event profiles. 29 Mitoxantrone Mitoxantrone is indicated for reducing neurologic disability and frequency of relapses in SPMS, PRMS, and worsening RRMS. 11 It may be considered for selected patients with worsening disease 51 but is used infrequently because of associated risks of acute myelogenous leukemia and cardiotoxicity, including decreased left ventricular ejection fraction (LVEF). 11,52 The recommended dosage is 12 mg/m 2 i.v. every 3 months. 11 Maximum cumulative exposure to mitoxantrone should not exceed 140 mg/m 2 (i.e., 2 3 years at the recommended dose). 11

7 managing multiple sclerosis reviews Early treatment of CIS delays disease progression In several randomized, placebo-controlled, Phase III trials using glatiramer acetate or IFNβ formulations, early treatment in patients with CIS demonstrated significant reductions in the risk of developing CDMS (Table 3) Emerging therapies for MS A number of other DMTs are being studied for use in MS (Table 4) Four additional oral therapies recently completed Phase III trials, and data are beginning to emerge. Oral cladribine selectively depletes T-cells and some types of B-cells and reduces inflammation. 60 In a completed placebo-controlled Phase III trial, cladribine significantly reduced relapse rates, lesions on MRI, and progression of disability. 60 Cladribine was associated with an increased risk of lymphocytopenias, severe infections/infestations, and malignancies. 60 In March 2011, FDA denied approval of cladribine a second time, calling for more safety data and analysis of risk-to-benefit ratio but said that the existing data are sufficient to support efficacy in reducing exacerbations and progression. 68 Results of Phase III trials for two other oral therapies, laquinimod and teriflunomide, were presented at the 2011 American Academy of Neurology (AAN) annual meeting. Both therapies significantly reduced annualized relapse rates and various MRI measures of disease compared with placebo. 61,62 Laquinimod 0.6 mg/day and teriflunomide 14 mg/day (but not 7 mg/day) also significantly reduced progression of disability. 61,62 Both therapies were well tolerated, with no increase in serious adverse events compared with placebo. 61,62 Laquinimod was associated with reversible increases in liver enzyme levels without clinical evidence of liver dysfunction. 61 No alanine aminotransferase elevations occurred in the Phase III study of teriflunomide, 62 but these were observed in an earlier Phase II study. 69 Neither of these studies has been published in a peerreviewed journal, and FDA has not reviewed these therapies. A Phase III trial also has been completed for dimethyl fumarate; results will be reported at a future medical conference. 63 Managing MS relapse Patients should be encouraged to report all relapses to their health care provider because relapse frequency is factored into deciding whether to continue or change the patient s DMT. 70 Corticosteroids are the most commonly used treatment for MS relapse and can be given safely with MS DMTs. 71 Steroids speed clinical recovery but do not necessarily improve the extent of recovery. 70 (Recovery following a relapse may be complete or incomplete, regardless of treatment.) The most common corticosteroid regimen used consists of 3 to 5 days of methylprednisolone 500 to 1,000 mg/day i.v., sometimes followed by a 1- to 3-week oral prednisone taper. 70,71 Comparable doses of oral steroids are sometimes given instead of intravenous therapy; efficacy and safety are thought to be similar. 72 Benefits of corticosteroid treatment must be weighed against known risks, including mood changes, elevations in blood pressure and serum glucose levels, and gastrointestinal adverse effects. 70 Table 4. Investigational therapies for multiple sclerosis Multiple sclerosis therapy Status as of April 2011 Route of administration Cladribine One Phase III published; Oral additional data requested by FDA Laquinimod Phase III reported Oral Teriflunomide Phase III reported Oral Dimethyl Phase III recently Oral fumarate completed; data have not been reported Alemtuzumab Phase III ongoing Intravenous Daclizumab Phase III ongoing Intravenous Ofatumumab Phase II reported Intravenous Source: References Relative contraindications or conditions that at least require close monitoring include diabetes, hypertension, pregnancy, poorly controlled psychiatric disorders, peptic ulcer, history of steroid intolerance, or concomitant use of warfarin sodium. 70,71 Steroids should not be used long term to treat MS. 71 A recent guideline from AAN concludes that plasmapheresis may be effective for steroid-refractory relapses but is not effective in SPMS or PPMS. 73 This procedure, also called plasma exchange, involves removing red blood cells and other components from the patient s blood, exchanging the plasma with donor plasma or albumin solution, and then restoring the patient s other blood components. 73 Improving mobility in MS The only pharmacologic therapy approved by FDA specifically and exclusively for walking is dalfampridine. Indicated to improve walking in patients with MS, dalfampridine is a potassium channel blocker and may restore conduction in demyelinated nerve fibers. 74 Dalfampridine was evaluated in two randomized, placebo-controlled, Phase III trials, with 301 patients given active treatment for 14 weeks and 239 patients treated for 9 weeks, respectively. 75,76 The primary outcome measure was walking speed. In both studies, dalfampridine significantly increased the proportion of patients who showed response on the Timed 25-Foot Walk test: 35% vs. 8%, respectively (P < ), in the first trial 75 and 43% vs. 9%, respectively (P < ), in the second trial. 76 Adverse effects included urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, and a potential increased risk of seizure, particularly at higher-than-recommended doses. 74 Dalfampridine is available as a 10-mg extended-release tablet for oral administration. The maximum dose is 10 mg twice daily. 74 Patients should be told to take the two doses 12 hours apart and not to take a double dose if they miss a dose. 74 Dalfampridine tablets should be swallowed whole not broken, crushed, or chewed either with or without food. 74 Dal- june 2011 Pharmacy Today 69

8 reviews managing multiple sclerosis fampridine is contraindicated for patients who have a history of seizures, have moderate to severe renal impairment, or are already taking compounded 4-aminopyridine (the active ingredient in dalfampridine). 74 Dalfampridine and 4-aminopyridine are not bioequivalent and cannot be substituted. Tell me more! The National MS Society website ( index.aspx) has a wealth of information for patients and clinicians about MS, including strategies for managing the disease and its many symptoms. Assess your knowledge (continued) T.G. s health care provider prescribes IFNβ-1b 250 µg s.c. administered every other day. During a pharmacy consultation, the pharmacist reviews the injection training for the product and discusses the importance of adherence. During the next year, T.G. is largely adherent to treatment. During a follow-up medication therapy management visit, she tells the pharmacist that a recent MRI showed no new lesions and that she has had no new neurologic symptoms. She says she has minor flulike symptoms after each injection. Because she has been doing well and finds the adverse effects bothersome, she questions whether she should continue on medication at all and, if she does, whether she can switch to the new oral MS medication she heard about so she does not have to self-inject. 3. What advice would you give her about whether to continue/discontinue or switch treatment? The pharmacist s role Pharmacists can play an important role in facilitating optimal use of MS medications. Pharmacists can collaborate with health care providers in making treatment recommendations and monitoring for treatment response and adverse events. Patients starting on a DMT require reinforcement of learning regarding proper dosing and administration (Table 5). 29,38,77 79 Table 5. Injection training Follow the protocol in the Medication Guide; product preparation, dosing schedule, and recommended injection technique vary by product Wash and dry your hands, then clean injection site with an alcohol wipe; let it dry before injecting Rotate injection sites, per Medication Guide Do not inject into red, bruised, infected, or irritated sites Use autoinjector (available free of charge from manufacturer) Inject medication at room temperature Ensure adequate needle penetration into subcutaneous tissues (or intramuscular tissue for IFNβ-1a intramuscular injectable) Do not rub or massage injection area on same day as glatiramer acetate injection Properly dispose of all used syringes; never reuse a syringe Ice the area before/after injection for IFN or warm the skin with a heat pack before injecting glatiramer acetate Suggest the patient ask his/her health care provider about smaller length/gauge needles Abbreviation used: IFN, interferon. Source: References 29, 38, and Pharmacists can be a great resource for patients with injection anxieties who may require extra support and assistance. 29 Pharmacists also can provide strategies for managing adverse effects, as discussed above. Finally, a key opportunity exists for pharmacists to improve MS outcomes by promoting adherence to DMT. Promoting adherence Between 17% and 41% of MS patients stop taking DMTs, usually within the first 2 years. 80 In a longitudinal prospective study of 97 MS patients taking DMT, nearly three-quarters missed at least one dose during the study period (January 2002 to April 2005), more than one-half missed doses on at least two occasions, and 10% missed more than 10 doses in any 6-month period. 81 Nearly 20% had stopped taking any treatment by the end of follow-up. 81 Taking less than recommended doses can lead to more disease activity, both clinically and on MRI. 80 Reasons for nonadherence include perceived lack of efficacy, adverse events, injection fears, laboratory abnormalities, depression, forgetting doses, denial of illness, treatment impact on lifestyle, cost, cognitive and physical barriers to performing injections, socioeconomic and cultural factors, and lack of support. 29,80,82 Where can patients go for answers? Direct patients to the Ask the Doctor forum at the MS Foundation website ( where questions and concerns are addressed by a panel of health professionals. Pharmacists can help improve adherence by establishing realistic patient expectations, providing education to the patient and family, and helping to manage adverse effects of therapy. 29 Patients need education that DMTs are not a cure, are not likely to eliminate existing symptoms or disability, and mitigate but do not eliminate future disease activity. 82 Although it may sound obvious, patients also should be reminded that these therapies work only if patients take them, preferably consistently. Over time, pharmacists should reinforce to the patient the need to continue treatment even if no disease activity is apparent or if relapses have occurred, both of which are likely to lead patients to consider discontinuing. 82 The pharmacist also should provide support by acknowledging the difficulty of adhering consistently to long-term medication use. 29 Medication therapy management (MTM) services should be offered to patients with MS, 1 including review of medications, assessment of patient knowledge and concerns, and education on key MS topics. 83 MTM has been shown to improve adherence and patients perceptions of their ability to manage health, as well as reduce relapses in MS. 83 Summary MS is a chronic inflammatory and neurodegenerative disease characterized by demyelination and axonal damage. The exact causes of MS are not fully understood but likely involve a combination of genetic and environmental factors. CIS is a single, symptomatic neurologic episode consistent with MS. Diagnosis of CDMS requires the presence of at least two lesions on MRI separated by time and space. Treatment of CIS and MS should 70 Pharmacy Today june

9 managing multiple sclerosis reviews be initiated as early as possible with one of the injectable DMTs to reduce the frequency of relapse, disease activity evident on MRI, and progression of disability. Patients should be counseled about proper injection technique and the need for adherence. Patients with inadequate response to IFNβ and/or glatiramer acetate may be treated with natalizumab or fingolimod, which offer excellent efficacy but require closer monitoring for potential adverse events. Patients should be encouraged to report all relapses to help determine the need for more aggressive treatment. Acute relapses may be managed with corticosteroids to speed recovery. Dalfampridine is not a DMT but may help improve walking and mobility in patients with MS. Assess your knowledge case study responses 1. CIS is a single episode that is consistent with MS, and she may be experiencing her first MS event. However, with one clinical event plus a normal MRI, she does not meet criteria for dissemination in space and time, so she cannot be given a full diagnosis of MS at this time. 2. Yes, patients with CIS should receive first-line MS DMTs, which may prevent or postpone conversion to CDMS. First-line therapy for a patient with CIS includes IFNβ-1a, IFNβ-1b, or glatiramer acetate. 3. She should continue on her current treatment regimen. Treatment should be continued indefinitely unless benefit is clearly lacking or adverse effects are intolerable or if better therapy becomes available; changes to another therapy should be made only if a medical reason exists. 51 The oral treatment she referred to, fingolimod, is not FDA approved for patients with CIS. It might be considered later if she has additional relapses and signs of disease activity despite continued adherence to IFNβ. References 1. Lipsy RJ, Schapiro RT, Prostko CR. Current and future directions in MS management: key considerations for managed care pharmacists. J Manag Care Pharm. 2009;15(9 suppl A):S National Multiple Sclerosis Society. Who gets MS? Accessed at March 14, Calabresi PA. Multiple sclerosis and demyelinating conditions of the central nervous system. In: Goldman L, Ausiello AA, Eds. Cecil medicine. 23rd ed. Philadelphia: Saunders; 2007: Dhib-Jalbut S. Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology. 2007;68(22 suppl 3):S National Multiple Sclerosis Society. What is multiple sclerosis? Accessed at March 14, Zivadinov R, Weinstock-Guttman B, Hashmi K, et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology. 2009;73: Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73: Sayao A-L, Devonshire V, Tremlett H. Longitudinal follow-up of benign multiple sclerosis at 20 years. Neurology. 2007;68: Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69: Tysabri [package insert]. Cambridge, MA: Biogen Idec; Novantrone [package insert]. Rockland, MD: EMD Serono; Avonex [package insert]. Cambridge, MA: Biogen Idec; Betaseron [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; Extavia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; Rebif [package insert]. Rockland, MA; EMD Serono; National Multiple Sclerosis Society. Kurtzke expanded disability status scale (EDSS). Accessed at search-results/index.aspx?q=kurtzke+expanded+disability+stat us+scale+(edss)&x=0&y=0&start=0&num=20, March 14, IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43: UBC MS/MRI Study Group, IFNB Multiple Sclerosis Study Group, Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43: PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352: Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39: PRISMS Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-beta- 1a in relapsing MS. Neurology. 2001;56: Kappos L, Traboulsee A, Constantinescu C, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsingremitting MS. Neurology. 2006;67: Uitdehaag B, Constantinescu C, Cornelisse P, et al. Impact of exposure to interferon beta-1a on outcomes in patients with relapsing-remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study. Ther Adv Neurol Disord. 2011;4: Bermel RA, Weinstock-Guttman D, Bourdette D, et al. Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler. 2010;16: Ebers GC, Reder AT, Traboulsee A, et al. Long-term follow-up of the original interferon beta-1b trial in multiple sclerosis: design and lessons from a 16-year observational study. Clin Ther. 2009;31: Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVI- DENCE trial. Neurology. 2002;59: Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359: Clanet M, Radue WE, Kappos L, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology. 2002;59: Brandes DW, Callender T, Lathi E, et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin. 2009;25: Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74(suppl 1):S june 2011 Pharmacy Today 71

10 reviews managing multiple sclerosis 31. Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebocontrolled trial. Neurology. 1995;45: Ford C, Goodman AD, Johnson K, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16: Cadavid D, Wolansky S, Cook S, et al. Betaseron versus Copaxone in multiple sclerosis with triple-dose gadolinium and 3 Tesla MRI Endpoints (BECOME): announcement of secondary clinical outcomes. Abstract presented at the 23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis and 12th annual conference of Rehabilitation in MS (RIMS), October 11 14, 2007, Prague, Czech Republic. 35. Wolansky L, Cook S, Skurnick J, et al. Betaseron vs. Copaxone in MS with triple-dose gadolinium and 3-T MRI Endpoints (BE- COME): announcement of final primary study outcome. Abstract presented at the 23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis and 12th annual conference of Rehabilitation in MS (RIMS), October 11 14, 2007, Prague, Czech Republic. 36. O Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsingremitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8: Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7: Shared Solutions. Your Copaxone injection guide. Accessed at March 14, Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362: Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; Kappos L, Radue EW, O Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362: ClinicalTrials.gov. Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis (FREE- DOMS II). Accessed at NCT ?term=, March 14, Novartis Pharmaceuticals. Gilenya risk evaluation and mitigation strategy (REMS). Accessed at DrugSafety/PostmarketDrugSafetyInformationforPatientsand- Providers/UCM pdf, April 10, Bielekova B, Becker BL. Monoclonal antibodies in MS: mechanisms of action. Neurology. 2010;74(suppl 1):S Polman CH, O Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354: National Multiple Sclerosis Society. Tysabri (natalizumab). Accessed at what-we-know-about-ms/treatments/medications/natalizumab/ index.aspx, March 14, Pharmacy Today june Yousry TA, Majr EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354: ODS Natalizumab RiskMAP Review Team. Tysabri (natalizumab) risk management program. Accessed at dockets/ac/06/briefing/ b1_01_06fdaods(riskmap). pdf, March 9, National Multiple Sclerosis Society. Expert opinion paper: changing therapy in relapsing multiple sclerosis: considerations and recommendations of a task force of the national multiple sclerosis society. Accessed at &y=0&start=0&num=20, April 10, National Multiple Sclerosis Society. Disease management consensus statement: management of MS-related fatigue. Accessed at about-multiple-sclerosis/treatments/download.aspx? id=8, March 25, Marriott JJ, Miyasaki JM, Gronseth G, O Connor PW. Evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010;74: Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374: Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343: Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357: Drugs.com. REFLEX study results show treatment with Rebif delays conversion to MS in patients wit first clinical signs of the disease. Accessed at March 14, Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67: Kinkel RP, Kollman C, O Connor P, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006;66: Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8: Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362: Comi G, Jeffery D, Kappos L, et al. Oral laquinimod reduced relapse rate and delayed progression of disability in ALLEGRO, a placebo-controlled phase III trial for relapsing-remitting multiple sclerosis. Abstract presented at the 63rd annual meeting of the American Academy of Neurology, April 9 16, 2011, Honolulu, HI. 62. Miller A, O Connor P, Wolinsky JS, et al. Clinical and MRI outcomes from a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses. Abstract presented at the 63rd annual meeting of the American Academy of Neurology, April 9 16, 2011, Honolulu, HI.

11 managing multiple sclerosis reviews 63. Biogen Idec. Biogen Idec announces positive top-line results from the first phase 3 trial investigating oral BG-12 (dimethyl fumarate) in multiple sclerosis. Accessed at com/press_release_details.aspx?id=5981&reqid= , April 28, ClinicalTrials.gov. Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, Study One (CARE-MS I). Accessed at www. clinicaltrials.gov/ct2/show/nct ?term=alemtuzumab+a ND+phase+III+AND+multiple+sclerosis&rank=2, March 24, ClinicalTrials.gov. Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, Study One (CARE-MS I). Accessed at MS+II+AND+alemtuzumab&rank=1, March 24, Phase III clinical trial using daclizumab for relapsing remitting multiple sclerosis initiated. Immunotherapy. 2010;2: Drugs.com. Genmab announces results of ofatumumab Phase II study in multiple sclerosis. Accessed at trials/genmab-announces-results-ofatumumab-phase-ii-studymultiple-sclerosis html, March 24, Gever J. FDA turns down cladribine for MS. Accessed at www. medpagetoday.com/neurology/multiplesclerosis/25137, March 24, O Connor PW, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66: Thrower BW. Relapse management in multiple sclerosis. The Neurologist. 2009;15(1): National Multiple Sclerosis Society. Recommendations regarding corticosteroids in the management of multiple sclerosis. Accessed at aspx?id=553, March 24, Burton JM, O Connor PW, Hohol M, et al. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2009;CD Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76: Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009;373: Goodman AD, Brown TR, Edwards KR, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68: FDA. Medication guide. Interferon beta-1a (Avonex). Accessed at March 24, Bayer HealthCare Pharmaceuticals. Medication guide: Betaseron. Accessed at Betaseron_Medication_Guide.pdf, March 25, FDA. Medication guide (Rebif) interferon beta-1a. Accessed at ucm pdf, March 24, Clerico M, Barbero P, Contessa G, et al. Adherence to interferonbeta treatment and results of therapy switching. J Neurol Sci. 2007;259: Tremlett H, Van der Mei I, Pittas F, et al. Adherence to the immunomodulatory drugs for multiple sclerosis: contrasting factors affect stopping drug and missing doses. Pharmacoepidemiol Drug Saf. 2008;17: Cohen BA. Adherence to disease-modifying therapy for multiple sclerosis. International Journal of MS Care. 2006;(February suppl): Stockl KM, Shin JS, Gong S, et al. Improving patient self-management of multiple sclerosis through a disease therapy management program. Am J Manag Care. 2010;16: june 2011 Pharmacy Today 73

12 reviews managing multiple sclerosis CPE exam Instructions: The assessment test for this activity must be taken online; please see CPE information below for further instructions. There is only one correct answer to each question. This CPE activity will be available online at no later than June 30, Conduction of nerve impulses is impaired in multiple sclerosis (MS) as a result of: a. Destruction of myelin and the underlying axon. b. Depletion of dopamine and serotonin. c. Damage to sodium/potassium pumps. d. Dysfunctional receptors on dendrites. 2. The most common initial presentation of MS is: a. Progressive-relapsing MS b. Primary-progressive MS c. Relapsing-remitting MS (RRMS) d. Secondary-progressive MS (SPMS) 3. According to the McDonald criteria, depending on magnetic resonance imaging (MRI) findings, the earliest possible point at which CDMS can be diagnosed is: a. At the first clinical episode. b. 30 days after a first clinical episode. c. 60 days after a first clinical episode. d. At the time of a second clinical episode. 4. Comparative trials suggest that which of the following interferon (IFN) therapies may have the least potent efficacy but a more mild safety profile? a. IFNβ-1b 250 µg s.c. every other day b. IFNβ-1a 22 µg s.c. every other day c. IFNβ-1a 44 µg s.c. every other day d. IFNβ-1a 30 µg i.m. every week 5. In a 15-year follow-up of RRMS patients taking glatiramer acetate: a. Efficacy generally wore off over time. b. More than one-half progressed to SPMS. c. More than 80% continued to walk without assistive devices. d. More than 75% showed progression on the expanded disability severity scale. 6. Which of the following MS therapies works by trapping lymphocytes in secondary lymph organs, preventing them from entering the circulation and the CNS? a. IFNβ b. Glatiramer acetate c. Fingolimod d. Cladribine 7. Which of these MS therapies requires enrollment into a special program for monitoring because of an increased risk of progressive multifocal leukoencephalopathy? a. Fingolimod b. Natalizumab c. Glatiramer acetate d. Mitoxantrone 8. A patient who was recently diagnosed with MS asks you which therapy you would recommend. You tell her that the most commonly used first-line agents with long-term safety records are: a. Mitoxantrone or one of the IFNβ formulations. b. Glatiramer acetate or fingolimod. c. Natalizumab or an IFNβ product. d. An IFNβ product or glatiramer acetate. 9. Which of the following is a rare but characteristic adverse effect of glatiramer acetate? a. Flulike symptoms b. Depression c. Chest pain/palpitations d. Thrombocytopenia CPE information To obtain 2.0 contact hours of CPE credit (0.2 CEUs) for this activity, complete and submit the CPE exam online at education. A Statement of Credit will be awarded for a passing grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before June 15, 2014, can receive credit. Your Statement of Credit will be available online immediately upon successful completion of the CPE exam. CPE instructions: Get your documentation of credit now! Completing a posttest at is as easy as Go to Online CPE Quick List and click on the title of this activity. 2. Log in. APhA members enter your user name and password. Not an APhA member? Just click Create one now to open an account. No fee is required to register. 3. Successfully complete the CPE exam and evaluation form to gain immediate access to your documentation of credit. Live step-by-step assistance is available Monday through Friday 8:30 am to 5:00 pm ET at APhA Member Services at APhA (2742) or by ing InfoCenter@pharmacist.com. 74 Pharmacy Today june

13 managing multiple sclerosis reviews 10. In the case study described in the main text, the pharmacist should tell the patient that she can ameliorate her flulike symptoms by: a. Stopping IFN for 3 months (i.e., drug holiday ). b. Taking analgesics at the time of injection or within an hour. c. Administering IFN cold, right from the refrigerator. d. Permanently cutting the IFN dose by one-half. 11. Which of the following is the recommended first-line treatment for acute relapse? a. Intravenous methylprednisolone b. Glatiramer acetate c. IFNβ-1b or IFNβ-1a d. Plasmapheresis 12. To date, this medication, although proven effective, has been associated with an increased risk of lymphocytopenias, severe infections/infestations, and malignancies and therefore FDA approval has been rejected until more safety data become available. a. Laquinimod b. Teriflunomide c. Dimethyl fumarate d. Cladribine 13. Which of the following therapies is indicated to improve walking in patients with MS? a. Natalizumab b. Dalfampridine c. Glatiramer acetate d. Fingolimod 14. When explaining the need for adherence to MS disease-modifying therapy (DMT), the pharmacist should convey that long-term adherence will: a. Eventually cure MS. b. Reverse existing disability and symptoms. c. Reduce relapse frequency and rate of progression. d. Prevent the need for a wheelchair in the future. 15. MS DMTs should be injected: a. Into the thighs exclusively. b. Into the abdomen exclusively. c. Into the buttocks exclusively. d. Into rotating injection sites. june 2011 Pharmacy Today 75