Vumerity

— THERAPEUTIC CATEGORIES —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Vumerity Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Diroximel fumarate 231mg; delayed-release caps.

    How Supplied

    Del-rel caps—106 (Starter Pack), 120 (Maintenance Pack)

    How Supplied

    Vumerity 231 mg capsules have a white cap and a white body, printed with “DRF 231 mg” in black ink on the body. 

    Vumerity is available as follows:

    • 30-day Starter dose bottle x 106 capsules
    • 30-day Maintenance dose bottle x 120 capsules

    Storage

    Store at 20° C to 25° C (68° F to 77° F); excursions permitted to 15° C to 30° C (59° F to 86° F).

    Manufacturer

    Biogen

    Generic Availability

    NO

    Mechanism of Action

    The mechanism by which diroximel fumarate exerts its therapeutic effect in multiple sclerosis is unknown. The active metabolite of diroximel fumarate has been shown in vitro and in vivo to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in the cellular response to oxidative stress.

    Vumerity Indications

    Indications

    Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

    Vumerity Dosage and Administration

    Prior to Treatment Evaluations

    Obtain the following prior to treatment with Vumerity:

    • A complete blood cell count (CBC), including lymphocyte count
    • Serum aminotransferase, alkaline phosphatase, and total bilirubin levels  

     

    Adult

    Swallow whole. Initially 231mg twice daily for 7 days, then increase to maintenance dose of 462mg twice daily. If maintenance dose not tolerated, temporarily reduce back to initial dose. Within 4 weeks, resume maintenance dose; if not tolerated, consider discontinuing.

    Children

    Not established.

    Renal Impairment

    No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite [2-hydroxyethyl succinimide (HES)], use of Vumerity is not recommended in patients with moderate or severe renal impairment.

    Administration

    Do not crush or chew, or sprinkle the capsule contents on food.

    If taken with food, avoid a high-fat, high-calorie meal/snack; the meal/snack should contain no more than 700 calories and no more than 30 g fat.

    Vumerity Contraindications

    Contraindications

    Concomitant dimethyl fumarate.

    Vumerity Boxed Warnings

    Not Applicable

    Vumerity Warnings/Precautions

    Warnings/Precautions

    Obtain a CBC including lymphocyte count prior to initiation, after 6 months, and every 6–12 months thereafter; consider interruption if lymphocyte counts <0.5×109/L persist for >6 months. Pre-existing low lymphocyte counts: not studied. Monitor for herpes zoster, other serious opportunistic infections; evaluate and treat if occurs; consider withholding until infection resolved. Monitor serum aminotransferase, alkaline phosphatase, and total bilirubin prior to initiation and during treatment; discontinue if significant liver injury is suspected. Discontinue if anaphylaxis or angioedema occurs. Withhold and evaluate at first sign/symptom suggestive of PML. Administration with non-enteric coated aspirin (up to 325mg) or food may reduce incidence/severity of flushing. Moderate or severe renal impairment: not recommended. Pregnancy. Nursing mothers.

    Warnings/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.
    • 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. 

    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 ~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. Six percent (6%) of dimethyl fumarate patients and <1% of placebo patients experienced lymphocyte counts <0.5×109/L (lower limit of normal 0.91×109/L).
    • In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced prolonged, severe lymphopenia (defined as lymphocyte counts <0.5×109/L for at least six months); in this group of patients, the majority of lymphocyte counts remained <0.5×109/L with continued therapy.
    • 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 <0.5×109/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. Decisions about whether or not to restart Vumerity should be individualized based on clinical circumstances.

    Liver Injury 

    • Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate 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 were resolved upon treatment discontinuation. 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 (eg, warmth, redness, itching, and/or burning sensation).
    • In clinical trials of dimethyl fumarate, 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.Administration of Vumerity with food may reduce the incidence of flushing. Studies with dimethyl fumarate show that administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing.

    Pregnancy Considerations

    There is no adequate data on the developmental risk associated with the use of Vumerity or dimethyl fumarate in pregnant women. In animal studies, administration of diroximel fumarate during pregnancy or throughout pregnancy and lactation resulted in adverse effects on embryo-fetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposures.

    Nursing Mother Considerations

    There is 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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Vumerity and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. 

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established. 

    Geriatric Considerations

    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 Considerations

    No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite [2-hydroxyethyl succinimide (HES)], use of Vumerity is not recommended in patients with moderate or severe renal impairment.

    Vumerity Pharmacokinetics

    Absorption

    Following oral administration of Vumerity, the median tmax of monomethyl fumarate (MMF) is 2.5 to 3 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased dose proportionally in the recommended daily dose range (462 mg to 924 mg).

    Distribution

    The apparent volume of distribution for MMF is between 72 L and 83 L in healthy subjects after administration of Vumerity. Human plasma protein binding of MMF is 27-45% and independent of concentration.

    Metabolism

    In humans, diroximel fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, to the major active metabolite, MMF, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. Fumaric and citric acid, and glucose are the major metabolites of MMF in plasma.  

    Esterase metabolism of diroximel fumarate also produces 2-hydroxyethyl succinimide (HES), an inactive major metabolite.

    Elimination

    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. The terminal half-life of MMF is approximately 1 hour, and accumulation of MMF does not occur with multiple doses of Vumerity. HES is mainly eliminated in urine (58-63% of the dose was excreted as HES in urine).

    Vumerity Interactions

    Interactions

    Avoid concomitant alcohol, high-fat and/or high-calorie meal/snack.

    Interactions

    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 co-ingestion of ethanol does not induce dose dumping. The mean peak plasma MMF concentration for diroximel fumarate was decreased by 9% and 21%, when co-administered with 240 mL of 5% v/v and 40% v/v of ethanol, respectively.

    In an open-label, randomized, balanced, crossover study, co-administration of Vumerity with a high-fat, high-calorie meal (900-1000 calories, 50% of calories from fat) did not affect the AUC of MMF, but resulted in an approximately 44% reduction in Cmax compared to fasted state. The MMF Cmax with low-fat, low-calorie (350-400 calories, 10 to 15 g fat) and medium-fat, medium-calorie (650-700 calories, 25 to 30 g fat) meals was reduced by approximately 12% and 25%, respectively.

    Relative to fasted state, the tmax of MMF was delayed from 2.5 hours (fasted state) to 4.5 hours (low-fat, low-calorie meal or a medium-fat, medium-calorie meal) and 7.0 hours (high-fat, high-calorie meal) in the fed state. There was no impact of low, medium, or high-fat meals on the AUC of MMF after administration of Vumerity. 

    Vumerity Adverse Reactions

    Adverse Reactions

    Flushing, abdominal pain, diarrhea, nausea, vomiting, pruritus, rash, albumin urine present; lymphopenia, liver injury.

    Vumerity Clinical Trials

    Clinical Trials

    The efficacy of Vumerity is based upon bioavailability studies in patients with relapsing forms of multiple sclerosis and healthy subjects comparing oral dimethyl fumarate delayed-release capsules to Vumerity delayed-release capsules (see full labeling).

    The clinical studies described below were conducted using dimethyl fumarate. 

    The efficacy and safety of dimethyl fumarate were demonstrated in two studies (Studies 1 and 2) that evaluated dimethyl fumarate taken either twice or three times a day in patients with relapsing-remitting multiple sclerosis (RRMS).

    Study 1: Placebo-Controlled Trial in RRMS 
    Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks. Patients were randomized to receive dimethyl fumarate 240 mg twice a day (n=410), dimethyl fumarate 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39 years, median time since diagnosis was 4 years, and median EDSS score at baseline was 2. The median time on study drug for all treatment arms was 96 weeks.

    Results showed that treatment with dimethyl fumarate achieved a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The following results are for dimethyl fumarate 240 mg twice daily vs placebo, respectively:

    • Proportion relapsing (primary endpoint): 27% vs 46% (relative risk reduction, 49%; P <.0001)

    • ARR: 0.172 vs 0.364 (relative reduction, 53%; P <.0001)

    • Proportion with disability progression: 16% vs 27% (relative risk reduction, 38%; P =.005)

    • Mean number of new or newly enlarging T2 lesions over 2 years: 2.6 vs 17 (P <.0001)

    • Percentage of patients with no new or newly enlarging lesions: 45% vs 27%

    • Number of Gd+ lesions at 2 years: 0.1 vs 1.8 (relative odds reduction, 90%; P <.0001)

    • Mean number of new T1 hypointense lesions over 2 years: 1.5 vs 5.6 (P <.0001)

    Study 2: Placebo-Controlled Trial in RRMS 
    Study 2 was a 2-year multicenter, randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. The primary endpoint was the annualized relapse rate at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression as defined in Study 1. Patients were randomized to receive dimethyl fumarate 240 mg twice a day (n=359), dimethyl fumarate 240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to 2 years. The median age was 37 years, median time since diagnosis was 3 years, and median EDSS score at baseline was 2.5. The median time on study drug for all treatment arms was 96 weeks.

    Results showed that treatment with dimethyl fumarate achieved a statistically significant effect on the relapse and MRI endpoints described above and the 240 mg three times daily dose showed no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The following results are for dimethyl fumarate 240 mg twice daily vs placebo, respectively:

    • ARR: 0.224 vs 0.401 (relative reduction, 44%; P <.0001)

    • Proportion relapsing: 29% vs 41% (relative risk reduction, 34%; P =.002)

    • Proportion with disability progression: 13% vs 17% (relative risk reduction, 21%; P =.25)

    • Mean number of new or newly enlarging T2 lesions over 2 years: 5.1 vs 17.4 (P <.0001)

    • Percentage of patients with no new or newly enlarging lesions: 27% vs 12%

    • Number of Gd+ lesions at 2 years: 0.5 vs 2.0 (relative odds reduction, 74%; P <.0001)

    • Mean number of new T1 hypointense lesions over 2 years: 3.0 vs 7.0 (P <.0001)

    Vumerity Note

    Not Applicable

    Vumerity Patient Counseling

    Patient Counseling

    Dosage and Administration 

    • Inform patients that they will be provided a starter dose bottle: one capsule twice a day for the first 7 days and then two capsules twice a day thereafter.
    • Advise patients to take Vumerity as instructed.
    • Inform patients to swallow Vumerity capsules whole and intact.
    • Inform patients to not crush, chew, or sprinkle capsule contents on food.
    • Inform patients that they should avoid a high-fat, high-calorie meal/snack at the time they take Vumerity. If taken with food, the meal/snack should contain no more than 700 calories and no more than 30 g fat.
    • Advise patients to avoid co-administration of Vumerity with alcohol. 

    Anaphylaxis and Angioedema 

    • Advise patients to discontinue Vumerity and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema. 

    Progressive Multifocal Leukoencephalopathy 

    • Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received dimethyl fumarate, and therefore may occur with Vumerity.
    • Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months.
    • Inform the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML.
    • Inform the patient that 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. 

    Herpes Zoster and Other Serious Opportunistic Infections 

    • Inform patients that herpes zoster and other serious opportunistic infections have occurred in patients who received dimethyl fumarate and therefore may occur with Vumerity.
    • Instruct the patient of the importance of contacting their doctor if they develop any signs or symptoms. 

    Lymphocyte Counts 

    • Inform patients that Vumerity may decrease lymphocyte counts. A blood test should be obtained before they start therapy. Blood tests are also recommended after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. 

    Liver Injury 

    • Inform patients that Vumerity causes liver injury.
    • Instruct patients treated with Vumerity to report promptly to their healthcare provider any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
    • A blood test should be obtained before patients start therapy and during treatment, as clinically indicated. 

    Flushing and Gastrointestinal (GI) Reactions 

    • Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time.
    • Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions.
    • Advise patients experiencing flushing that taking Vumerity with food (avoid highfat, high-calorie meal or snack) or taking a non-enteric coated aspirin prior to taking Vumerity may help. 

    Pregnancy 

    • Instruct patients that if they are pregnant or plan to become pregnant while taking Vumerity they should inform their healthcare provider associated with herpes zoster or other serious opportunistic infections.

    Cost Savings Program

    The Vumerity patient support program is available here.

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