Treatment considerations for your VUMERITY patients

Treatment considerations based on your patients' individual needs1-3
Half-life1

  • With a terminal half-life of ~1 hour for monomethyl fumarate (MMF), VUMERITY is eliminated from the body without the need for accelerated elimination

  • Accumulation of MMF does not occur with multiple doses of VUMERITY

  • MMF is mainly eliminated as carbon dioxide in the expired air with only trace amounts (less than 0.3% of the total dose) recovered in urine

  • 2-hydroxyethyl succinimide (HES), the major circulating inactive drug-related compound in humans, is mainly eliminated in urine
Drug-to-drug interactions1

  • In a study conducted with dimethyl fumarate, no relevant effects of MMF on oral contraceptive exposure were observed when administered with a combined oral contraceptive (norelgestromin and ethinyl estradiol). No interaction studies have been performed with oral contraceptives containing other progestogens

  • Diroximel fumarate (DRF) metabolism does not involve cytochrome P450 (CYP) enzymes; therefore, no clinically meaningful interactions are expected when administered with CYP inhibitors or inducers

  • Aspirin, when administered approximately 30 minutes before dimethyl fumarate (DMF), did not alter the pharmacokinetics of MMF

  • Administration of VUMERITY at the same time with 5% v/v and 40% v/v ethanol did not alter total MMF exposure relative to administration with water, demonstrating that the coingestion of ethanol does not induce dose dumping. The mean peak plasma MMF concentration for DRF was decreased by 9% and 21% when co-administered with 240 mL of 5% v/v and 40% v/v of ethanol, respectively

  • VUMERITY is contraindicated in patients currently taking DMF, which is also metabolized to MMF. VUMERITY may be initiated the day following discontinuation of DMF

Antibody response to certain vaccines

In an MS PATHS study, patients on fumarates had a similar IgG response to COVID-19 vaccination as patients not on DMT4

IgG antibody response of MS patients on fumarates was similar to those not on DMT at the time of vaccination

reactive IgG rates in patients on fumarates and those not on DMT in initial postvaccination testing

Study description4,5:

  • 322 participants with MS (33 primary progressive, 87 clinically isolated syndrome, 154 relapsing remitting, 45 secondary progressive, 3 missing) enrolled in the MS PATHS network in the US, Germany, and Spain were recruited to voluntarily provide blood samples 30 days prior to first vaccine dose and 28 to 90 days after final vaccine dose

  • Blood samples were taken with or without corresponding prevaccination sample after 2 injections of AstraZeneca, Pfizer, or Moderna vaccines, or 1 injection of the Johnson & Johnson vaccine

  • 37 participants received fumarates (32 DMF, 5 DRF) and 28 received no DMT

  • An IgG index ≥1 was considered positive according to the manufacturer’s instruction for the immunoassay kit used for the sample analysis. Sample analysis is ongoing

  • Endpoint was IgG response to the SARS-CoV-2 spike protein

Limitations:

  • Study included a relatively small number of participants

  • Lack of prevaccination samples precluded exclusion of patients previously infected with SARS-CoV-2

  • The study did not measure neutralizing antibody response, and T-cell response to SARS-CoV-2 was not assessed

DMF did NOT attenuate antibody responses to the nonlive vaccines in another study1

Icon of a germ
Nonlive vaccines included in the study:

Tetanus toxoid-containing vaccine

Pneumococcal polysaccharide vaccine

Meningococcal vaccine

Study description:

  • A randomized, open-label study examined the use of DMF (which has the same active metabolite as VUMERITY) and tetanus toxoid, pneumococcal polysaccharide, and meningococcal vaccines in patients between the ages 27 and 55 years with relapsing forms of MS

  • At the time of vaccination, 38 patients underwent treatment with DMF and 33 patients underwent treatment with nonpegylated interferon

Limitations:

  • A small patient population was included in this study

  • The impact of these findings on vaccine effectiveness in this patient population is unknown

  • The safety and effectiveness of live or live-attenuated vaccines administered simultaneously with VUMERITY or DMF have not been assessed

    •  

Treatment considerations for your patients of childbearing age1
Pregnancy1

  • There are no adequate data on the developmental risk associated with the use of VUMERITY or DMF (which has the same active metabolite as VUMERITY) in pregnant women

  • Instruct patients who are pregnant or plan to become pregnant while taking VUMERITY that they should inform their healthcare professional
Lactation1

  • There are no data on the presence of diroximel fumarate or metabolites (MMF, HES) in human milk. The effects on the breastfed infant and on milk production are unknown
Contraception1

  • In a study conducted with dimethyl fumarate, no relevant effects of MMF on oral contraceptive exposure were observed when administered with a combined oral contraceptive (norelgestromin and ethinyl estradiol)

  • No interaction studies have been performed with oral contraceptives containing other progestogens

Treatment considerations in other populations1
Pediatric use

  • Safety and effectiveness in pediatric patients have not been established
Geriatric use

  • Clinical studies of dimethyl fumarate and VUMERITY did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients
Renal impairment

  • No dosage adjustment is necessary in patients with mild renal impairment

  • VUMERITY is not recommended in patients with moderate or severe renal impairment

Taking all these considerations into account may help inform your treatment decisions

Watch leading HCPs discuss their experiences treating with VUMERITY

Indication

VUMERITY® (diroximel fumarate) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Important Safety Information

CONTRAINDICATIONS

VUMERITY is contraindicated in patients

  • With known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY. Reactions may include anaphylaxis and angioedema
  • Taking dimethyl fumarate

WARNINGS AND PRECAUTIONS

Anaphylaxis and Angioedema

  • VUMERITY can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in patients taking dimethyl fumarate (which has the same active metabolite as VUMERITY) have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue VUMERITY and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema

Progressive Multifocal Leukoencephalopathy

  • Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate (which has the same active metabolite as VUMERITY). PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial
  • PML has occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9 x 109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8×109/L persisting for more than 6 months
  • At the first sign or symptom suggestive of PML, withhold VUMERITY and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes
  • Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present

Herpes Zoster and Other Serious Opportunistic Infections

  • Serious cases of herpes zoster have occurred in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY), including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on VUMERITY for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered
  • Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment
  • Consider withholding VUMERITY treatment in patients with herpes zoster or other serious infections until the infection has resolved

Lymphopenia

  • VUMERITY may decrease lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (which has the same active metabolite as VUMERITY), mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with dimethyl fumarate or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 109/L or ≤0.5 x 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years)
  • In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced prolonged, severe lymphopenia (defined as lymphocyte counts <0.5 x 109/L for at least six months); in this group of patients, the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. In these patients with prolonged, severe lymphopenia, the median time for lymphocyte counts to return to normal after discontinuing dimethyl fumarate was 96.0 weeks
  • In these controlled and uncontrolled clinical studies, among patients who did not experience prolonged, severe lymphopenia during treatment, the median times for lymphocyte counts to return to normal after discontinuing dimethyl fumarate were as follows:
    • 4.3 weeks in patients with mild lymphopenia (lymphocyte count ≥0.8 x 109/L) at discontinuation,
    • 10.0 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to <0.8 x 109/L) at discontinuation, and
    • 16.7 weeks in patients with severe lymphopenia (lymphocyte count <0.5 x 109/L) at discontinuation.
  • Neither VUMERITY nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts
  • Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with VUMERITY, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of VUMERITY in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if VUMERITY is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution

Liver Injury

  • Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate (which has the same active metabolite as VUMERITY) in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients
  • Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials with dimethyl fumarate
  • Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with VUMERITY and during treatment as clinically indicated. Discontinue VUMERITY if clinically significant liver injury induced by VUMERITY is suspected

Flushing

  • VUMERITY may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials of dimethyl fumarate (which has the same active metabolite as VUMERITY), 40% of dimethyl fumarate-treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization

Serious Gastrointestinal Reactions

  • Serious gastrointestinal (GI) reactions, including perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes, have been reported in the postmarketing setting with the use of fumaric acid esters, including VUMERITY, with or without concomitant aspirin use. The majority of these events have occurred within 6 months of fumaric acid ester treatment initiation. In controlled clinical trials, the incidence of serious gastrointestinal adverse reactions was 1% in patients treated with dimethyl fumarate; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%)
  • Monitor patients, promptly evaluate, and discontinue VUMERITY for new or worsening severe gastrointestinal signs and symptoms

ADVERSE REACTIONS

  • The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate (which has the same active metabolite as VUMERITY) were flushing, abdominal pain, diarrhea, and nausea
  • Gastrointestinal adverse reactions: Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with dimethyl fumarate compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with dimethyl fumarate
  • Hepatic transaminases: An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate was seen primarily during the first six months of treatment and most patients with elevations had levels <3 times the upper limit of normal (ULN) during controlled trials. There were no elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with dimethyl fumarate or placebo
  • Eosinophilia adverse reactions: A transient increase in mean eosinophil counts was seen during the first 2 months of therapy

USE IN SPECIFIC POPULATIONS

Pregnancy

  • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VUMERITY during pregnancy. Encourage patients to enroll by calling
    1-833-569-2635 or visiting www.blossomspregnancyregistry.com

Renal Impairment

  • No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite, use of VUMERITY is not recommended in patients with moderate or severe renal impairment

Please see full Prescribing Information.

DMF=dimethyl fumarate; DMT=disease-modifying therapy; DRF=diroximel fumarate; HES=2-hydroxyethyl succinimide; IgG=immunoglobulin G; MMF=monomethyl fumarate; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

References: 1. VUMERITY Prescribing Information. Cambridge, MA: Biogen. 2. Ross A, et al. Counseling Points. 2012;8(3):2-16. 3. Pardo G, et al. J Neurol. 2017;264(12):2351-2374. 4. Cohen JA, et al. Mult Scler. 2022;28(7):1131-1137. 5. Atellica IM Instructions for Use. Siemens Healthineers; 2022. Accessed June 24, 2021. https://www.fda.gov/media/146931

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