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Recognizing and Overcoming Potential Barriers to Oral Medications for MS

Harold Moses, Jr, MD

Department of Neurology, Neuroimmunology Division, Vanderbilt University Medical Center, Nashville, Tennessee

Several disease-modifying treatment options are available for patients with multiple sclerosis (MS). Typically, MS patients have been treated with injections or IV medications, but newer oral agents are also beneficial. However, barriers to the use of oral medications exist, and clinicians and patients must weigh the positive and negative aspects when choosing treatments.

Considerations for Using New Oral Treatments

Over the past 20 years, practitioners and patients have dealt with the steady introduction of new MS therapies, including oral medications. With newly diagnosed patients, clinicians face the challenge of how to discuss treatment options with individuals who are unaware of the goals and expectations associated with a serious, chronic medical condition. With the introduction of additional therapies, this discussion requires more time and consideration of factors related to different mechanisms of action and potential side effects. Factors to consider for oral drugs, which should be discussed not only with newly diagnosed patients but also with those who are interested in switching treatment, include family planning, comorbidities, aspects of tolerability, and possible sequencing of therapies.

Another challenge related to newer therapies is that insurers may limit options. Insurance companies will likely exert substantial pressure on organizations to establish algorithms for the treatment of MS. The care of patients with MS requires an individualized approach, and some patients will need access to potentially restricted therapies. For the benefit of patients, health care providers should engage insurers, specialty pharmacies, and pharmacy benefit managers to provide access to all FDA-approved therapies for MS.

Oral Agents Approved for MS Treatment

Three FDA-approved disease-modifying oral agents are currently available for the treatment of MS: fingolimod, teriflunomide, and dimethyl fumarate (see Table 1). Each drug offers advantages and disadvantages.

Fingolimod. Fingolimod is a high affinity sphingosine-1-phosphate receptor agonist derived from myriocin.1 Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate, which retains certain lymphocytes in the lymph nodes, causing reduction of lymphocytes in peripheral blood.2 Thus, fewer activated lymphocytes move into the CNS where they would cause inflammatory damage. In addition, fingolimod may stimulate the repair process of glial cells and precursor cells after injury.3

AV 1. Potential Adverse Effects and Safety Monitoring of Oral Medications for MS (0:53)

AV 1. Selected Symptoms of Multiple Sclerosis

The main advantage of fingolimod, which received FDA approval in 2010, is that it is a once-daily oral therapy.2 Generally, patients feel more comfortable taking an oral medication than an injection or IV, which can be painful and require extra office visits. Additionally, a review4 of 2 pivotal studies of fingolimod in patients with relapsing-remitting MS found that annualized relapse rates were significantly lower for fingolimod, 0.5 mg/d, versus IFNβ-1a (0.16 vs 0.33; P = .001) and fingolimod, 0.5 mg/d, versus placebo (0.18 vs 0.40; P = .001). A retrospective study5 of patients with MS who were unresponsive to IFNβ treatment examined the results of switching patients to either fingolimod or glatiramer acetate in real-world settings. Patients who switched to fingolimod had a 59% lower probability of relapse and 62% fewer relapses per year compared with those who switched to glatiramer acetate.

However, fingolimod has several disadvantages related to adverse effects and monitoring requirements (AV 1).6 Due to the risk of bradycardia and heart block, 6-hour observation following the first dose is necessary. Patient monitoring is also needed due to the risk of macular edema, liver impairment, and infections (eg, varicella zoster virus). Certain agents may cause negative interference with fingolimod and should not be used concurrently (eg, ketoconazole, live vaccines).2 Common side effects are headaches, influenza, diarrhea, back pain, and cough. Hypertension has been reported as well, as have fatal infections including disseminated zoster.2 Another possible risk may be PML, which the FDA is investigating.7 The FDA has assigned fingolimod to pregnancy category C (AV 2).6

AV 2. Pregnancy Risks Associated With MS Therapies (1:04)

AV 2. Clinician and Patient Factors That Influence Treatment Decisions

Teriflunomide. Teriflunomide, the active metabolite of leflunomide, an agent used to treat rheumatoid arthritis, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme required by white blood cells.8 As an immunomodulatory agent with anti-inflammatory properties, teriflunomide may improve MS by inhibiting lymphocyte proliferation.8,9

Teriflunomide was approved by the FDA in 2012 as a once-daily oral therapy.8 In a randomized trial,10 researchers found that teriflunomide (7 mg/d and 14 mg/d) reduced the annualized relapse rate versus placebo (0.37 for teriflunomide at both doses vs 0.54 for placebo; P = .001). A phase 3 trial11 also showed that patients receiving teriflunomide, 14 mg/d or 7 mg/d, had lower annualized relapse rates (0.32 and 0.39) compared with placebo (0.50).

Teriflunomide has various disadvantages, including its potential for liver toxicity, which is why monthly liver function testing is required for the first 6 months of use. Infections may result from a decrease in white blood cell counts, and hypertension, elevated potassium, and acute renal failure have also been associated with this medication.6 Other common adverse reactions include hair thinning, influenza, diarrhea, nausea, and paresthesia.8 Caution should be used in diabetic patients and those over the age of 60 years. Teriflunomide has been assigned pregnancy category X by the FDA; women should not become pregnant and men should not father a child while taking the drug.6 Finally, the half-life of teriflunomide is 2 weeks, but the drug may be present in some patients for as long as 2 years after discontinuation (cholestyramine or activated charcoal hastens elimination).6

Dimethyl fumarate. The mechanism of action for dimethyl fumarate’s benefit in patients with MS is currently unknown.12 Dimethyl fumarate appears to modulate immune-cell responses, and it activates the nuclear factor (erythroid-derived 2)-like 2 pathway in vitro and in vivo, a pathway that is involved in the response to oxidative stress.6,12 The drug also works by downregulating adhesion molecules so that harmful T cells are less likely to enter the brain. Glutathione depletion and subsequent induction of the anti-inflammatory stress protein HO-1 is thought to be one of the mechanisms responsible for the immunomodulatory actions of dimethyl fumarate.13

The advantages of dimethyl fumarate, which was approved in early 2013 as a twice-daily oral tablet, are its favorable efficacy data and safety profile. For example, in a phase 3 study14 involving patients with relapsing-remitting MS, the annualized relapse rates at 2 years were 0.17 in the twice-daily dimethyl fumarate group compared with 0.36 in the placebo group (P = .001). Another phase 3 trial15 found lower annualized relapse rates for twice-daily dimethyl fumarate versus placebo (0.22 vs 0.40) and reduced numbers of new or enlarging T2 lesions for dimethyl fumarate compared with placebo.

Up to 40% of patients taking dimethyl fumarate experience flushing (warmth, redness, itching, and/or burning sensations).6 GI symptoms, including abdominal pain, diarrhea, vomiting, and dyspepsia, are common.12 Cases of PML have been reported in psoriasis patients taking the parent drug of dimethyl fumarate,16 and caution should be used with dimethyl fumarate in patients with baseline lymphopenia and/or prior immunosuppressant use. In the first year, a mean reduction in peripheral lymphocyte count of about 30% may occur, requiring baseline complete blood count and yearly checks.6 Like fingolimod, dimethyl fumarate is in pregnancy category C.6


Newly diagnosed MS patients have a variety of treatment choices, and selecting therapy with patients will require even more time and effort from the prescribing physician. A consensus about the initial choice and potential sequencing of older and newer agents is unlikely to occur; some of those decisions will be influenced by insurance coverage. Established patients will also be interested in the newer oral therapies, and health care providers should discuss all available options.

Clinical Points
  • Consider that oral medications may be better treatment options than injections or IV for certain patients with MS
  • Know the efficacy and safety profiles of the 3 FDA-approved oral agents fingolimod, teriflunomide, and dimethyl fumarate
  • Explain the advantages and disadvantages of oral agents to patients

CNS = central nervous system
GI = gastrointestinal
IFNβ = interferon beta
IV = intravenous
MS = multiple sclerosis
PML = progressive multifocal leukoencephalopathy
TB = tuberculosis

Drug Names

dimethyl fumarate (Tecfidera), fingolimod (Gilenya), glatiramer acetate (Copaxone), interferon β-1a (Avonex and Rebif), interferon β-1b (Betaseron and Extavia), natalizumab (Tysabri), teriflunomide (Aubagio)

Take the CME posttest.
  1. 1. Chiba K, Adachi K. Sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis. Pharmaceuticals (Basel). 2012;5(5):514–528. PubMed
  2. 2. Gilenya (fingolimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9. Accessed April 17, 2014.
  3. 3. Horga A, Montalban X. FTY720 (fingolimod) for relapsing multiple sclerosis. Expert Rev Neurother. 2008;8(5):699–714. PubMed
  4. 4. Goldenberg MM. Multiple sclerosis review. PT. 2012;37(3):175–184. PubMed
  5. 5. Bergvall N, Makin C, Lahoz R, et al. Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study. PLoS One. 2014;9(2):e88472. PubMed
  6. 6. Rommer PS, Zettl UK, Kieseier B, et al. Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clin Exp Immunol. 2014;175(3):397–407. PubMed
  7. 7. FDA Drug Safety Communication: FDA investigating rare brain infection in patient taking Gilenya (fingolimod); August 29, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm366529.htm. Accessed April 17, 2014.
  8. 8. Aubagio (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corp; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4650d12c-b9c8-4525-b07f-a2d773eca155. Accessed April 17, 2014.
  9. 9. Garnock-Jones KP. Teriflunomide: a review of its use in relapsing multiple sclerosis. CNS Drugs. 2013;27(12):1103–1123. PubMed
  10. 10. O’Connor P, Wolinsky JS, Confavreaux C, et al, for the TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–1303. PubMed
  11. 11. Confavreux C, O’Connor P, Comi G, et al, for the TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–256. PubMed
  12. 12. Tecfidera (dimethyl fumarate) [package insert]. Cambridge, MA: Biogen Idec Inc; 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=665d7e74-036c-5f68-5b67-ab84b9b49151. Accessed April 17, 2014.
  13. 13. Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol. 2006;13(6):604–610. PubMed
  14. 14. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–1107. PubMed
  15. 15. Fox RJ, Miller DH, Phillips JT, et al, for the CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–1097. PubMed
  16. 16. Samson K. PML reported in patients taking psoriasis compounds sharing ingredient with oral MS drug. Neurology Today. 2013;13(11):6–7. doi:10.1097/01.nt.0000431669.47629.08.

CME Background Information

Supported by an educational grant from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation.


After completing this educational activity, you should be able to:

  • Balance positive and negative aspects of oral medications when choosing treatments for individual patients

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Moses is a consultant for Bayer, Biogen, Genzyme, Teva, and Questcor; has received grant/research support from Novartis, NIH, Biogen, Sanofi, and Genzyme; and is a member of the speaker’s/advisory boards for Questcor, Avanir, Teva, Biogen, and Bayer.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report was published in May 2014 and is eligible for AMA PRA Category 1 Credit™ through May 31, 2017. The latest review of this material was April 2014.

Statement of Need and Purpose

Multiple sclerosis (MS) affects over 2 million people worldwide and results in reduced quality of life, cognitive impairment, and physical disabilities. The medications initially approved for MS required patients to either self-administer injections or receive hospital-based intravenous infusions. However, the US Food and Drug Administration (FDA) has recently approved oral medications for MS, which has changed patients’ outlook toward MS therapies, and using oral medications may have a positive impact on their quality of life. Oral agents have several benefits, including convenience, ease of use, and greater comfort with taking a pill versus administering an injection, but carry risks as well, especially for potentially serious side effects. Further, long-term safety and efficacy of these new agents remain unknown. Therefore, switching patients to oral medications on the basis of convenience is not a sufficient reason for the change. Because the landscape of MS treatment is changing rapidly, health care providers need information on all of the available treatments to help their patients receive optimal care. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on multiple sclerosis.

Disclosure of Off-Label Usage

Dr Moses has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration-approved labeling has been presented in this activity.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.


This Neurology Report is derived from the planning teleconference series “The Impact of Oral Medications on the Treatment of Multiple Sclerosis,” which was held in November 2013 and March 2014 and supported by educational grants from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.