Diroximel Fumarate (Monograph)
Brand name: Vumerity
Drug class: Fumarates
Introduction
Fumaric acid derivative with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).1 3 Metabolized to the same active metabolite (monomethyl fumarate [MMF]) as dimethyl fumarate.1 2 3
Uses for Diroximel Fumarate
Multiple Sclerosis
Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.1
Diroximel fumarate is metabolized to the same pharmacologically active metabolite (monomethyl fumarate [MMF]) as dimethyl fumarate; therefore, efficacy is based on established bioequivalence to dimethyl fumarate.1 2 Efficacy and safety of diroximel fumarate expected to be similar to dimethyl fumarate, which has been shown to substantially reduce relapse rates and new or enlarging T2 lesions.1 2 17 18 19
Compared with dimethyl fumarate, diroximel fumarate produces equivalent exposure to the active metabolite (MMF) but is associated with improved GI tolerability.3 17
Diroximel fumarate is one of several disease-modifying therapies used in the management of relapsing forms of MS.17 76 77 Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression.76 78
The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI lesion activity.76 Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.76 77
Diroximel Fumarate Dosage and Administration
General
Patient Monitoring
-
Because of risk of lymphopenia, obtain CBC (including lymphocyte count) prior to initiating therapy, at 6 months, and then every 6–12 months thereafter as clinically indicated.1
-
Because of possible hepatic injury, perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to initiating therapy and then as clinically indicated.1
-
Monitor for new or worsening severe GI signs and symptoms during therapy.1
Premedication and Prophylaxis
-
Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to diroximel fumarate may reduce the incidence or severity of flushing.1
Administration
Oral Administration
Administer orally twice daily with or without food.1
Administration with food may reduce incidence of flushing; however, avoid administration with a high-fat, high-calorie meal or snack.1 If taken with food, the meal or snack should contain no more than 700 calories and no more than 30 g fat.1
Swallow delayed-release capsules whole and intact.1 Do not crush or chew capsules; do not open and sprinkle capsule contents on food.1
Dosage
Adults
Relapsing Forms of Multiple Sclerosis
Oral
Initially, 231 mg twice daily.1 After 7 days, increase to maintenance dosage of 462 mg twice daily.1
In patients not tolerating dosage of 462 mg twice daily, consider temporary reduction to 231 mg twice daily, and then resume recommended maintenance dosage of 462 mg twice daily within 4 weeks.1 If patient does not tolerate an increase back to recommended maintenance dosage, consider discontinuance of therapy.1
Special Populations
Hepatic Impairment
No dosage adjustment necessary.1 Although no studies have been conducted, hepatic impairment not expected to affect exposure to active metabolite.1
Renal Impairment
No dosage adjustment necessary in patients with mild renal impairment.1 Not recommended in patients with moderate or severe renal impairment because of possibility of increased exposure to a major metabolite.1
Geriatric Patients
Manufacturer makes no specific dosage recommendations.1
Cautions for Diroximel Fumarate
Contraindications
-
Known hypersensitivity to diroximel fumarate or dimethyl fumarate, or to any excipients in the formulation.1
-
Concomitant use of dimethyl fumarate.1
Warnings/Precautions
Anaphylaxis and Angioedema
May cause anaphylaxis or angioedema after the first dose or at any time during therapy.1 Hypersensitivity reactions, including difficulty breathing, urticaria, and swelling of the throat and tongue reported with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate).1
Discontinue diroximel fumarate if any signs or symptoms of anaphylaxis or angioedema occur.1
Progressive Multifocal Leukoencephalopathy (PML)
PML, an opportunistic infection of the brain caused by the JC virus, reported in patients receiving dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate).1 PML has been reported with dimethyl fumarate in the setting of prolonged lymphopenia, including a fatal case of PML in a patient with MS who had lymphocyte counts <500/mm3 for 3.5 years.1
At the first sign or symptom suggestive of PML, immediately withhold therapy and perform appropriate diagnostic evaluation.1 MRI signs of PML may be apparent before clinical manifestations develop.1
Infectious Complications
Serious cases of herpes zoster and other opportunistic infections (viral, fungal, and bacterial) reported with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate); has occurred in patients with lymphopenia as well as in patients with normal lymphocyte counts.1 May occur at any time during therapy.1
Monitor for signs and symptoms of herpes zoster or other opportunistic infections.1 If any manifestations of such infections occur, promptly evaluate and treat patient appropriately.1 Consider interruption of therapy in patients with serious infections until infection resolves.1
Lymphopenia
May decrease lymphocyte counts.1 In clinical trials with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate), mean lymphocyte counts decreased by approximately 30% during the first year of therapy.1 Lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.1
Increased incidence of serious infections not observed in patients with decreased lymphocyte counts, but one case of PML developed in the setting of prolonged lymphopenia.1
Not studied in patients with preexisting low lymphocyte counts.1
Obtain CBC, including lymphocyte count, prior to initiation of therapy, at 6 months, then every 6–12 months during therapy as clinically indicated.1
In patients with lymphocyte counts <500/mm3 persisting for >6 months, consider interruption of therapy.1 Consider monitoring lymphocyte counts after the drug is discontinued until lymphopenia has resolved since lymphocyte recovery may be delayed.1
In patients with serious infections, consider withholding treatment until infection resolves.1 Consider patient's clinical circumstances when deciding whether to restart therapy.1
Hepatic Injury
Liver injury, sometimes requiring hospitalization, reported with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate).1 Liver function test abnormalities (e.g., elevations in serum aminotransferase concentrations to more than fivefold the ULN and elevations in total bilirubin concentrations to more than twofold the ULN) observed.1 Occurred within a few days to several months after initiation of therapy and resolved upon treatment discontinuance.1
No cases resulted in liver failure, liver transplantation, or death; however, abnormal liver function tests may predict serious liver injury.1
Perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to and during therapy as clinically indicated.1 Discontinue drug if liver injury suspected.1
Flushing
May cause flushing (e.g., warmth, redness, itching, burning sensation).1 In clinical trials of dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate), flushing was reported in 40% of patients who received the drug.1 Symptoms generally are mild to moderate, begin soon after initiating therapy, and improve or resolve over time.1
Administration with food or pretreatment with non-enteric-coated aspirin (up to a dose of 325 mg) 30 minutes before diroximel fumarate may reduce incidence and/or severity of flushing.1
Serious Gastrointestinal Reactions
Serious GI reactions (e.g., perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes) reported with use of fumaric acid esters, with or without concomitant aspirin use.1 Most have occurred within 6 months of fumaric acid ester initiation.1 Monitor patients, promptly evaluate, and discontinue diroximel fumarate for new or worsening severe GI signs and symptoms.1
Specific Populations
Pregnancy
No adequate data on developmental risk associated with use during pregnancy.1 Based on animal data, may cause fetal harm.1
A registry that monitors outcomes in pregnant women exposed to diroximel fumarate exists.1 Patients may enroll in the registry by calling 1-833-569-2635 or visiting [Web].1
Lactation
Not known whether diroximel fumarate or its metabolites are distributed into human milk.1
Effects on nursing infant or on milk production also not known.1
Consider benefits of breast-feeding along with the woman's clinical need for diroximel fumarate and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1
Pediatric Use
Safety and efficacy not established in pediatric patients.1
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1
Hepatic Impairment
Not studied in individuals with hepatic impairment; hepatic impairment not expected to affect systemic exposure to the active MMF metabolite.1
Dosage adjustment not necessary in patients with hepatic impairment.1
Renal Impairment
Dosage adjustment not necessary in patients with mild renal impairment.1
Not recommended in patients with moderate or severe renal impairment because of increased systemic exposure to the inactive major metabolite HES; data on long-term use not available.1
Common Adverse Effects
Adverse reactions reported with diroximel fumarate (≥10% and ≥2% more than placebo): Flushing, abdominal pain, diarrhea, and nausea.1
Adverse reactions reported with diroximel fumarate are similar to those with dimethyl fumarate.1
Drug Interactions
No potential drug interactions with diroximel fumarate or its main active metabolite, MMF, identified in CYP, P-glycoprotein, or protein-binding studies.1
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Alcohol |
Decreased peak plasma MMF concentrations; however, total MMF exposure not affected1 |
|
Aspirin |
Administration of non-enteric coated aspirin 325 mg approximately 30 minutes prior to dimethyl fumarate (which is metabolized to same active metabolite as diroximel fumarate) over 4 days did not alter MMF pharmacokinetics but reduced incidence and severity of flushing1 5 14 |
|
Dimethyl fumarate |
Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF)1 |
Concomitant use contraindicated1 Diroximel fumarate may be initiated the day following discontinuance of dimethyl fumarate1 |
Oral Contraceptives |
Dimethyl fumarate (which is metabolized to same active metabolite as diroximel fumarate) had no clinically important effects on ethinyl estradiol or norelgestromin1 Interaction studies with dimethyl fumarate or diroximel fumarate not conducted with oral contraceptives containing other progestogens1 |
|
Vaccines |
Non-live vaccines: Concomitant exposure to dimethyl fumarate (which is metabolized to same active metabolite as diroximel fumarate) did not attenuate antibody response to tetanus toxoid-containing vaccine, pneumococcal polysaccharide vaccine, or meningococcal vaccine relative to antibody response in interferon-treated patients; impact of these findings on vaccine effectiveness not known1 Live or live-attenuated vaccines: Safety and efficacy in patients receiving diroximel fumarate not evaluated1 |
Diroximel Fumarate Pharmacokinetics
Following oral administration, undergoes rapid and extensive metabolism by esterases to its active metabolite, monomethyl fumarate (MMF).1 Because diroximel fumarate is not quantifiable in plasma after oral administration, all pharmacokinetic analysis were performed with plasma MMF concentrations.1
Absorption
Bioavailability
Diroximel fumarate 462 mg delayed-release capsules and dimethyl fumarate 240 mg delayed-release capsules are bioequivalent in terms of systemic exposure to MMF.2 3
Median time to peak plasma MMF concentrations is 2.5–3 hours.1
Accumulation of MMF does not occur with multiple oral doses.1
Food
High-fat, high-calorie meal (900–1000 calories, 50% of calories from fat): Peak plasma MMF concentrations decreased approximately 44% and time to peak plasma concentration delayed from 2.5 hours to 7 hours.1 No effect on AUC.1
Medium-fat, medium-calorie (650–700 calories, 25–30 g fat) meal: Peak plasma MMF concentrations decreased approximately 25% and time to peak plasma concentration delayed from 2.5 hours to 4.5 hours.1 No effect on AUC.1
Low-fat, low-calorie meal (350–400 calories, 10–15 g fat): Peak plasma MMF concentrations decreased approximately 12% and time to peak plasma concentration delayed from 2.5 hours to 4.5 hours.1 No effect on AUC.1
Distribution
Extent
Not known whether diroximel fumarate or its metabolites distribute into human milk.1
MMF distributes into the CNS.23
Plasma Protein Binding
MMF is 27–45% protein bound; protein binding is independent of concentration.1
Elimination
Metabolism
Extensively metabolized by esterases (present in GI tract, blood, and tissues) to MMF before reaching systemic circulation.1 Esterase metabolism of diroximel fumarate also produces 2-hydroxyethyl succinimide (HES), an inactive major metabolite.1
MMF is further metabolized by the tricarboxylic acid (TCA) cycle with no involvement of cytochrome P450 (CYP) pathways.1 The major metabolites of MMF in plasma are fumaric acid, citric acid, and glucose.1 1
Elimination Route
MMF is eliminated mainly by exhalation as carbon dioxide with <0.3% in urine.1
HES is eliminated mainly in urine (58-63% of the dose).1
Half-life
MMF: Approximately 1 hour.1
Special Populations
Exposure to HES (inactive metabolite) increased by 1.3, 1.8, or 2.7-fold in mild, moderate, or severe renal impairment, respectively; no clinically important changes in MMF exposure.1
Stability
Storage
Oral
Delayed-release Capsules
20–25°C (excursions permitted between 15–30°C).1
Actions
-
Exact mechanism of action in MS is unknown; immunomodulatory effect appears to be mediated by many cells of the immune system.1 7 9 11
-
MMF (active metabolite) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans.1 5 7 11 23 The Nrf2 pathway is involved in the cellular response to oxidative stress.1 23
-
Nrf2-dependent upregulation of antioxidant response genes by MMF may protect various cells and tissues, including some in the CNS, from experimental toxic oxidative stress.7 11 23
-
Activation of the Nrf2 pathway by fumaric acid derivatives also may inhibit proliferation of lymphocytes and hematopoietic stem cells.16 Dose-dependent reduction in peripheral lymphocytes occurs, with more pronounced reduction in CD8+ T-cell counts than in CD4+ T-cell counts;16 23 subsets of other lymphocytes (e.g., memory T-cells, B-cells, natural killer [NK] cells) also altered.23 Such alterations in the composition of peripheral lymphocytes are thought to shift the immune profile towards an anti-inflammatory state in patients with MS.23
-
MMF is a nicotinic acid receptor agonist in vitro.1 Nicotinic acid and fumaric acid derivatives can cause skin flushing; flushing reactions may be mediated by activation of hydroxy-carboxylic acid receptor 2 (HCA2) and involve formation of prostaglandins.12 14
Advice to Patients
-
Advise patients to read the manufacturer's patient information.1
-
Inform patients that when starting treatment with diroximel fumarate, they will receive a starter dose bottle, and that they should take 1 capsule twice a day for the first 7 days and then 2 capsules twice a day thereafter.1 Advise patients to take diroximel fumarate exactly as prescribed.1
-
Inform patients to swallow diroximel fumarate delayed-release capsules whole and intact, and not to crush, chew, or sprinkle the capsule contents on food.1 Inform patients that the capsules may be taken with or without food, but they should avoid a high-fat, high-calorie meal or snack.1 If taken with food, the meal or snack should contain ≤700 calories and ≤30 g fat.1 Advise patients to avoid concomitant administration of diroximel fumarate capsules with alcohol.1
-
Risk of anaphylaxis and angioedema.1 Advise patients to discontinue diroximel fumarate and seek immediate medical care if they develop signs and symptoms of anaphylaxis or angioedema (e.g., difficulty breathing, urticaria, swelling of the throat and tongue).1
-
Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received dimethyl fumarate, and therefore may occur with diroximel fumarate.1 Inform patients that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months.1 Immediately inform a clinician of any new or worsening symptoms suggestive of PML (e.g., progressive weakness on one side of the body; clumsiness of limbs; disturbance of vision; changes in cognition, memory, and orientation leading to confusion and personality changes) that have progressed over days to weeks.1
-
Risk of decreased lymphocyte counts.1 Stress importance of periodic monitoring of CBCs.1
-
Risk of herpes zoster and other serious opportunistic infections.1 Advise patients to contact a clinician if they develop any signs or symptoms associated with herpes zoster or other infections.1
-
Risk of liver injury.1 Advise patients to immediately report any possible manifestations, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice; importance of patients receiving liver function tests prior to and during treatment as clinically indicated to monitor for such effects.1
-
Inform patients that flushing and adverse GI reactions (e.g., abdominal pain, diarrhea, and nausea) commonly occur during diroximel fumarate therapy, particularly at the initiation of treatment, and that they may decrease over time.1 Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions (e.g., GI hemorrhage).1 Advise patients that taking diroximel fumarate with food (avoiding high-fat, high-calorie meal or snack) or taking a non-enteric-coated aspirin prior to taking diroximel fumarate may be helpful in certain cases.1
-
Stress importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 A registry that monitors outcomes in pregnant women exposed to diroximel fumarate exists.1 Patients may enroll in the registry by calling 1-833-569-2635 or visiting [Web].1
-
Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., infections).1
-
Inform patients of other important precautionary information.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Diroximel fumarate is available through a specialty pharmacy network.6 Clinicians may consult the Vumerity website at [Web] or call 800-456-2255 for specific availability information.6
.6
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules, delayed-release |
231 mg |
Vumerity |
Biogen |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions August 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
References
1. Biogen. Vumerity (diroximel fumarate) capsules prescribing information. Cambridge, MA; 2024 Mar.
2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 0211855Orig1s000: Summary Review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211855Orig1s000SumR.pdf
3. Naismith RT, Wolinsky JS, Wundes A et al. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study. Mult Scler. 2019; :1352458519881761. http://www.ncbi.nlm.nih.gov/pubmed/31680631?dopt=AbstractPlus
4. Naismith RT, Wundes A, Ziemssen T et al. Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study. CNS Drugs. 2020; 34:185-196. http://www.ncbi.nlm.nih.gov/pubmed/31953790?dopt=AbstractPlus
5. Biogen. Tecfidera (dimethyl fumarate) delayed-release capsules prescribing information. Cambridge, MA; 2020 Feb.
6. Biogen. Vumerity start form. From the Vumerity website. Accessed 2020 April 21. https://www.vumerityhcp.com/en_us/home/start-vumerity/start-vumerity.html
7. Stangel M, Linker RA. Dimethyl fumarate (BG-12) for the treatment of multiple sclerosis. Expert Rev Clin Pharmacol. 2013; 6:355-62. http://www.ncbi.nlm.nih.gov/pubmed/23927662?dopt=AbstractPlus
8. Albrecht P, Bouchachia I, Goebels N et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation. 2012; 9:163. http://www.ncbi.nlm.nih.gov/pubmed/22769044?dopt=AbstractPlus
9. Lin SX, Lisi L, Dello Russo C et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro. 2011; 3:. http://www.ncbi.nlm.nih.gov/pubmed/21382015?dopt=AbstractPlus
11. Scannevin RH, Chollate S, Jung MY et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012; 341:274-84. http://www.ncbi.nlm.nih.gov/pubmed/22267202?dopt=AbstractPlus
12. Hanson J, Gille A, Offermanns S. Role of HCA2 (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin. Pharmacol Ther. 2012; 136:1-7. http://www.ncbi.nlm.nih.gov/pubmed/22743741?dopt=AbstractPlus
13. Anon. Dimethyl fumarate (Tecfidera) for multiple sclerosis. Med Lett Drugs Ther. 2013; 55:45-7.
14. Sheikh SI, Nestorov I, Russell H et al. Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther. 2013; 35:1582-94. http://www.ncbi.nlm.nih.gov/pubmed/24139424?dopt=AbstractPlus
16. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K et al. Reduction of CD8+ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2015; 2:e76. http://www.ncbi.nlm.nih.gov/pubmed/25738172?dopt=AbstractPlus
17. . Drugs for multiple sclerosis. Med Lett Drugs Ther. 2021; 63:42-48. http://www.ncbi.nlm.nih.gov/pubmed/33976089?dopt=AbstractPlus
18. 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; 367:1098-107. http://www.ncbi.nlm.nih.gov/pubmed/22992073?dopt=AbstractPlus
19. Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012; 367:1087-97. http://www.ncbi.nlm.nih.gov/pubmed/22992072?dopt=AbstractPlus
23. Mills EA, Ogrodnik MA, Plave A et al. Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Front Neurol. 2018; 9:5. http://www.ncbi.nlm.nih.gov/pubmed/29410647?dopt=AbstractPlus
76. Rae-Grant A, Day GS, Marrie RA et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018; 90:777-788. http://www.ncbi.nlm.nih.gov/pubmed/29686116?dopt=AbstractPlus
77. Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence summary. Available from National MS Society website. http://www.nationalmssociety.org/getmedia/1e64b96c-9e55-400e-9a64-0cdf5e2d60fe/summaryDMTpaper_-final
78. National MS Society. Disease-modifying therapies for MS (updated March 2022). Available from National MS Society website. https://nms2cdn.azureedge.net/cmssite/nationalmssociety/media/msnationalfiles/brochures/brochure-the-ms-disease-modifying-medications.pdf
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