Specialty Pharmacy Considerations for Oral Multiple Sclerosis Therapies

Multiple sclerosis treatment options have expanded dramatically over the past several years. In addition to subcutaneous and intravenous medications, there are now 3 disease-modifying oral therapies available in the United States.

The multiple sclerosis (MS) treatment landscape has changed dramatically over the past few years. In addition to the subcutaneous and intramuscular disease-modifying treatments (such as interferon beta-1a, interferon beta-1b, and glatiramer acetate) and the intravenously infused products (such as mitoxantrone and natalizubmab), there are also 3 oral disease-modifying therapies currently available in the United States for MS. Oral agents Gilenya (fingolimod; Novartis), Aubagio (teriflunomide; Genzyme), and Tecfidera (dimethyl fumarate; Biogen Idec) continue to reshape the MS treatment paradigm.

GILENYA (FINGOLIMOD)^1-4

Gilenya (fingolimod), the first oral disease-modifying therapy for MS, was approved by the FDA on September 21, 2010. Fingolimod is the first approved drug to act as a sphingosine 1-phosphate receptor modulator. The fingolimod dose is 0.5 mg by mouth once daily. The primary end point in the FREEDOMS pivotal placebo controlled trial involving 1272 patients with relapsing-remitting MS was reduction in relapse rates. Relapse rates were reduced in this study from an annualized rate of 0.40 for those on placebo to 0.18 for those taking fingolimod 0.5 mg daily (a comparative reduction of 54%).

In the TRANSFORMS trial, fingolimod safety and efficacy was evaluated versus interferon beta-1a intramuscular (Avonex). The annualized relapse rate in those taking fingolimod was 0.16, compared with 0.33 in those on Avonex (a comparative reduction of 52%). The most common adverse events associated with fingolimod include headache, influenza, diarrhea, back pain, increases in liver function tests, and cough. On August 29, 2013, the FDA issued a drug safety communication to alert the public that a patient in Europe diagnosed with possible MS had developed progressive multifocal leukoencephalopathy (PML). This was the first case of PML reported following the administration of fingolimod to a patient who had not previously received natalizumab. Novartis states that approximately 71,000 patients worldwide have been treated with fingolimod to date. The FDA is working with Novartis to review all available information about the PML occurrence and will communicate its final conclusions and recommendations after the FDA evaluation is complete.

FINGOLIMOD SPECIALTY PHARMACY CONSIDERATIONS¹

• A medication guide is required with each dispense of fingolimod therapy.
• Fingolimod can be taken with or without food.
• Fingolimod requires first-dose monitoring for at least 6 hours post-initiation of the medication.

° Monitor pulse and blood pressure hourly

° Perform an ECG prior to therapy initiation and at the end of the observation period

° Detailed instructions for first-dose monitoring are available in the prescribing information

• Fingolimod is pregnancy category C and should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

° Instruct patients of childbearing potential to use reliable contraception during treatment with fingolimod and up to 2 months post therapy, as the drug may cause fetal harm if pregnancy occurs during treatment

° A pregnancy registry is available at (877) 598-7237

• Fingolimod may cause hypertension, headache, influenza, diarrhea, back pain, and cough.
• Advise patient to report signs and symptoms of:

° Bradycardia, especially within the first 6 hours of administration

° Infection (a recent complete blood count [CBC] should be available before initiating treatment with fingolimod, and signs and symptoms of infection should be monitored 2 months after discontinuation)

° Respiratory distress or shortness of breath, as fingolimod can cause a decrease in pulmonary function

° Hepatic dysfunction (nausea, vomiting, abdominal pain, jaundice, or dark urine)

• Patients should receive an eye exam prior to therapy initiation as well as 3 to 4 months post therapy initiation to check for macular edema. Advise patient to report signs/symptoms of visual disturbances.
• Contraindications to fingolimod include:

° Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or class III/IV heart failure

° History or presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless patient has a pacemaker

° Baseline QTc interval of greater than or equal to 500 ms

° Treatment with class Ia or class III anti-arrhythmic drugs

AUBAGIO (TERIFLUNOMIDE)^5,6

Aubagio (teriflunomide) was approved by the FDA on September 12, 2012. It is a once-daily oral pyrimidine synthesis inhibitor and is the active metabolite of leflunomide. Therefore, it has both immunomodulating and anti-nflammatory properties. The recommended daily dose of teriflunomide is 7 mg or 14 mg orally once daily with or without food. The primary end point in the TEMSO pivotal phase III trial involving 1088 patients was reduction in relapse rate. Relapse rates were reduced in this study from an annualized rate of 0.539 for those in the placebo group to 0.369 for those patients taking teriflunomide 14 mg and to 0.370 for those patients taking teriflunomide 7 mg daily (a relative risk reduction of 31% for both the teriflunomide 14 mg and 7 mg groups compared with placebo). The most common adverse reactions seen in clinical trials included elevation of liver enzymes, alopecia, diarrhea, influenza, nausea, and paresthesia.

TERIFLUNOMIDE SPECIALTY PHARMACY CONSIDERATIONS⁵

• A medication guide is required for each dispense of teriflunomide therapy.
• Teriflunomide can be taken with or without food.
• The most common reason for discontinuation due to adverse events in clinical studies was alopecia. Alopecia occurred in 13% of patients in the teriflunomide 14 mg group, in 10% in the teriflunomide 7 mg group, and 3% in the placebo group.
• Teriflunomide is pregnancy category X and is contraindicated in pregnancy as it may increase the risk of teratogenic effects or fetal death when administered to pregnant women.

° Women of childbearing potential should not be started on teriflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception

° Prior to starting teriflunomide, patients must be fully counseled on the potential for serious risk to the fetus

° The patient must be advised that if there is any delay in onset of menses or other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing

° A pregnancy registry is available at (800) 745-4447

° Women receiving teriflunomide therapy who wish to become pregnant must discontinue teriflunomide and verify that teriflunomide plasma concentrations are less than 0.02 mg/L

• Teriflunomide is eliminated slowly from the plasma and takes 8 months on average to reach plasma concentrations of less than 0.02 mg/L, although in some patients it may take as long as 2 years. An accelerated elimination procedure can be used at any time after the discontinuation of teriflunomide.
• Accelerated Elimination Procedures

° Administration of cholestyramine 8 grams every 8 hours for 11 days; if 8 grams 3 times a day is not tolerated, 4 grams 3 times a day can be used

° Administration of 50 grams oral activated charcoal powder every 12 hours for 11 days

° If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly

° Use of the accelerated elimination procedure may result in return of disease activity if the patient had been responding to teriflunomide treatment

• Advise patient to report signs and symptoms of:

° Infection (a recent CBC should be available before initiating treatment with teriflunomide and further monitoring should be based on signs and symptoms of infection)

° Peripheral neuropathy

° Acute renal failure or hyperkalemia

° Severe skin reaction

° Increases in blood pressure

° Hepatic dysfunction (nausea, vomiting, abdominal pain, jaundice, or dark urine)

° Respiratory effects

• Monitoring parameters to assess safety of teriflunomide therapy include:

° Obtain transaminase and bilirubin levels within 6 months prior to initiation of teriflunomide and monitor alanine aminotransterase levels at least monthly for 6 months after starting teriflunomide

° Obtain a CBC within 6 months before initiating therapy and monitor for signs and symptoms of infection

° Screen patients for latent tuberculosis infection with a tuberculin skin test

° Check blood pressure before start of therapy and periodically thereafter

• Teriflunomide is contraindicated in patients with severe hepatic impairment, pregnancy, and patients who are currently being treated with leflunomide.

TECFIDERA (DIMETHYL FUMARATE)⁷

Tecfidera (dimethyl fumarate) was approved by the FDA on March 27, 2013, to treat adults with relapsing forms of MS. The recommended starting dose of dimethyl fumarate is 120 mg orally twice a day for 7 days. After 7 days, a maintenance dose of 240 mg twice a day is recommended. The prescribing information contains data from 2 phase III trials in relapsing-remitting MS, known as DEFINE and CONFIRM. In the DEFINE trial, 410 patients in the dimethyl fumarate 240 mg twice daily group had an annualized relapse rate of 0.172 compared with 0.364 for the 408 patients in the placebo group (a relative reduction of 53%).

In the CONFIRM trial, 359 patients in the dimethyl fumarate 240 mg twice daily group had an annualized relapse rate of 0.224 compared with 0.401 for the 363 patients in the placebo group (a relative reduction of 44%). The most common adverse events seen in the clinical trials for dimethyl fumarate included flushing and gastrointestinal events such as diarrhea, nausea, and abdominal pain. These events were most common at the start of therapy and usually decreased over time.

DIMETHYL FUMARATE SPECIALTY PHARMACY CONSIDERATIONS⁷

• Dimethyl fumarate can be taken with or without food.
• A CBC within 6 months prior to treatment is recommended before initiation of therapy to identify patients with a preexisting low lymphocyte count. Dimethyl fumarate may decrease lymphocyte counts and a CBC should be repeated annually and as clinically indicated.
• Dimethyl fumarate may cause flushing such as warmth, redness, itching, and/or a burning sensation.

° In clinical trials, 40% of dimethyl fumarate patients experienced flushing

° Flushing symptoms generally began soon after initiation of treatment and usually improved or resolved over time

° Administration of dimethyl fumarate with food may reduce the incidence of flushing

• Administration of dimethyl fumarate with food may also reduce gastrointestinal problems such as nausea, vomiting, diarrhea, stomach pain, and indigestion.
• Dimethyl fumarate is pregnancy category C and should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

° A pregnancy registry is available at (800) 456-2255

• There are no known contraindications to dimethyl fumarate at this time. SPT

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References:

1. Gilenya [prescribing information]. Novartis; May 2012. www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf. Accessed September 3, 2013.

2. AAN 2009: Oral fingolimod superior to interferon beta 1-a in RRMS. Medscape Med News. May 4, 2009. www.medscape.com/viewarticle/702487. Accessed September 3, 2013.

3. Fingolimod. National Multiple Sclerosis Society. www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/medications/fingolimod/index.aspx. Accessed September 3, 2013.

4. FDA Drug Safety Communication: FDA investigating rare brain infection in patient taking Gilenya (fingolimod). US Food and Drug Administration; August 29, 2013. www.fda.gov/Drugs/DrugSafety/ucm366529.htm. Accessed September 3, 2013.

5. Aubagio [prescribing information]. Genzyme Corporation; September 2012. http://products.sanofi.us/aubagio/aubagio.pdf. Accessed September 3, 2013.

6. FDA approves new multiple sclerosis treatment Aubagio. US Food and Drug Administration; September 12, 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm319277.htm. Accessed September 3, 2013.

7. Tecfidera [prescribing information]. Biogen Idec; May 2013. www.tecfidera.com/pdfs/full-prescribing-information.pdf. Accessed September 2, 2013.

The above information is a selective summary of publicly available information and is accurate as of the date of writing. Please consult the sources for complete reference information. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc.

About the Author

Stacey Ness, PharmD, RPh, MSCS, AAHIVP, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence, and persistency programs, and chronic disease cost optimization strategies. Stacey is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, National Association of Specialty Pharmacy, Specialty Pharmacy Certification Board, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist, a credentialed HIV pharmacist, and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, New Jersey.