DIROXIMEL: 10,626 Adverse Event Reports & Safety Profile

VUMERITY contains diroximel fumarate. The chemical name of diroximel fumarate is 2-Butenedioic acid (2E)-, 1-[2-(2,5-dioxo-1-pyrrolidinyl)ethyl] 4-methyl ester, which has a molecular formula of C 11 H 13 NO 6 and molecular weight of 255.22. Diroximel fumarate has the following structure: Diroximel fumarate is a white to off-white powder that is slightly soluble in water. VUMERITY is provided as delayed-release capsules for oral administration. Each capsule contains 231 mg of diroximel fumarate and the following inactive ingredients: crospovidone, colloidal silicon dioxide, magnesium stearate (non-bovine), methacrylic acid and ethyl acrylate copolymer, microcrystalline cellulose, talc, and triethyl citrate. The capsule shell contains carrageenan, hypromellose, potassium chloride, and titanium dioxide. It is printed with black ink that contains iron oxide, potassium hydroxide, propylene glycol, and shellac.

Structural

Formula

AND USAGE VUMERITY 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. VUMERITY 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. ( 1 )

AND ADMINISTRATION Blood tests are required prior to initiation of VUMERITY ( 2.1 ) Starting dose: 231 mg twice a day, orally, for 7 days ( 2.2 ) Maintenance dose after 7 days: 462 mg (administered as two 231 mg capsules) twice a day, orally ( 2.2 ) Swallow VUMERITY capsules whole and intact. Do not crush, chew, or sprinkle capsule contents on food ( 2.3 ) Avoid administration of VUMERITY with a high-fat, high-calorie meal/snack ( 2.3 ) Avoid co-administration of VUMERITY with alcohol ( 2.3 )

2.1 Blood Tests Prior to Initiation of VUMERITY Obtain the following prior to treatment with VUMERITY: A complete blood cell count (CBC), including lymphocyte count <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . Serum aminotransferase, alkaline phosphatase, and total bilirubin levels <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

2.2 Dosing Information The starting dosage for VUMERITY is 231 mg twice a day orally.

After

7 days, the dosage should be increased to the maintenance dosage of 462 mg (administered as two 231 mg capsules) twice a day orally. Temporary dosage reductions to 231 mg twice a day may be considered for individuals who do not tolerate the maintenance dosage.

Within

4 weeks, the recommended dosage of 462 mg twice a day should be resumed. Discontinuation of VUMERITY should be considered for patients unable to tolerate return to the maintenance dosage. Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to VUMERITY dosing may reduce the incidence or severity of flushing [see Clinical Pharmacology ( 12.3 )].

2.3 Administration Instructions Swallow VUMERITY capsules whole and intact. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )]</span> . Avoid co-administration of VUMERITY with alcohol <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

2.4 Blood Tests to Assess Safety After Initiation of VUMERITY Obtain a complete blood cell count (CBC), including lymphocyte count, 6 months after initiation of VUMERITY and then every 6 to 12 months thereafter, as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span>. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels during treatment with VUMERITY, as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span>.

2.5 Patients With Renal Impairment No dosing adjustment is recommended in patients with mild renal impairment. VUMERITY is not recommended in patients with moderate or severe renal impairment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> .

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 [see Warnings and Precautions ( 5.1 )]. Taking dimethyl fumarate [see Drug Interactions ( 7.1 )] . Known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY ( 4 ) Co-administration with dimethyl fumarate ( 4 )

REACTIONS The following important adverse reactions are described elsewhere in labeling: Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.1 )]

Progressive Multifocal

Leukoencephalopathy [see Warnings and Precautions Section ( 5.2 )]

Herpes

Zoster and Other Serious Opportunistic Infections [see Warnings and Precautions ( 5.3 )] Lymphopenia [see Warnings and Precautions ( 5.4 )]

Liver

Injury [see Warnings and Precautions ( 5.6 )] Flushing [see Warnings and Precautions ( 5.6 )]

Serious Gastrointestinal

Reactions [see Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence for dimethyl fumarate [which has the same active metabolite as VUMERITY] ≥10% and ≥2% more than placebo) were flushing, abdominal pain, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described in the following sections were obtained using dimethyl fumarate delayed-release capsules, which has the same active metabolite as VUMERITY. In placebo controlled and uncontrolled clinical studies of dimethyl fumarate (which has the same active metabolite as VUMERITY), a total of 2513 patients have been followed for periods up to 13 years with an overall exposure equivalent to 11,318 person-years. A total of 1169 patients have received at least 5 years of treatment with dimethyl fumarate, and 426 patients have received at least 10 years of treatment with dimethyl fumarate.

Adverse

Reactions in Placebo-Controlled Trials with Dimethyl Fumarate In the two well-controlled studies demonstrating effectiveness, 1529 patients received dimethyl fumarate with an overall exposure of 2244 person-years [see Clinical Studies ( 14 )]. The adverse reactions presented in Table 1 below are based on safety information from 769 patients treated with dimethyl fumarate 240 mg twice a day and 771 placebo-treated patients. The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea.

Table

1: Adverse Reactions in Study 1 and 2 Reported for Dimethyl Fumarate at ≥2% Higher Incidence than Placebo Adverse Reactions Dimethyl Fumarate 240 mg Twice Daily (N=769) % Placebo (N=771) % Flushing 40 6 Abdominal pain 18 10 Diarrhea 14 11 Nausea 12 9 Vomiting 9 5 Pruritus 8 4 Rash 8 3 Albumin urine present 6 4 Erythema 5 1 Dyspepsia 5 3 Aspartate aminotransferase increased 4 2 Lymphopenia 2 <1 Gastrointestinal 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 clinical trial patients treated with dimethyl fumarate; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%).

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. Elevations of alanine aminotransferase and aspartate aminotransferase to ≥3 times the ULN occurred in a small number of patients treated with both dimethyl fumarate and placebo and were balanced between groups. 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 A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Adverse

Reactions in Clinical Studies with VUMERITY In clinical studies assessing safety in patients with RRMS, approximately 700 patients were treated with VUMERITY and approximately 490 patients received more than 1 year of treatment with VUMERITY. The adverse reaction profile of VUMERITY was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate.

6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of dimethyl fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal

Disorders: Acute pancreatitis; Gastrointestinal perforation, ulceration, obstruction, and hemorrhage [see Warnings and Precautions ( 5.7 )]

Hepatobiliary

Disorders: Liver function abnormalities (elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN) [see Warnings and Precautions ( 5.5 )]. Infections and Infestations: Herpes zoster infection and other serious opportunistic infections [See Warnings and Precautions ( 5.3 )]. Respiratory, Thoracic, and Mediastinal Disorders: Rhinorrhea Skin and Subcutaneous: Alopecia

AND PRECAUTIONS Anaphylaxis and Angioedema: Discontinue and do not restart VUMERITY if these occur. ( 5.1 )

Progressive Multifocal

Leukoencephalopathy (PML): Withhold VUMERITY at the first sign or symptom suggestive of PML. ( 5.2 )

Herpes

Zoster and Other Serious Opportunistic Infections: Consider withholding VUMERITY in cases of serious infection until the infection has resolved. ( 5.3 ) Lymphopenia: Obtain a CBC including lymphocyte count before initiating VUMERITY, after 6 months, and every 6 to 12 months thereafter. Consider interruption of VUMERITY if lymphocyte counts <0.5 × 10 9 /L persist for more than six months. ( 5.4 )

Liver

Injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating VUMERITY and during treatment, as clinically indicated. Discontinue VUMERITY if clinically significant liver injury induced by VUMERITY is suspected. ( 5.6 )

5.1 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.

5.2 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. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly &lt;0.5 × 10 9 /L for 3.5 years) while taking dimethyl fumarate <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span>. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly. PML has also occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (&lt;0.9 × 10 9 /L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts &lt;0.8×10 9 /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. Cases of PML diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be 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. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

5.3 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

5.4 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. Six percent (6%) of dimethyl fumarate patients and &lt;1% of placebo patients experienced lymphocyte counts &lt;0.5 × 10 9 /L (lower limit of normal 0.91 × 10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts &lt;0.8 × 10 9 /L or ≤0.5 × 10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly &lt;0.5 × 10 9 /L for 3.5 years) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced prolonged, severe lymphopenia, (defined as lymphocyte counts &lt;0.5 x 10 9 /L for at least six months); in this group of patients, the majority of lymphocyte counts remained &lt;0.5 x 10 9 /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 10 9 /L) at discontinuation, 10.0 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to &lt;0.8 x 10 9 /L) at discontinuation, and 16.7 weeks in patients with severe lymphopenia (lymphocyte count &lt;0.5 x 10 9 /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 × 10 9 /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.

5.5 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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.

5.6 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 &lt;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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

5.7 Serious Gastrointestinal Reactions Serious gastrointestinal 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%) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Monitor patients, promptly evaluate, and discontinue VUMERITY for new or worsening severe gastrointestinal signs and symptoms.

INTERACTIONS

7.1 Concomitant Dimethyl Fumarate VUMERITY is contraindicated in patients currently taking dimethyl fumarate, which is also metabolized to monomethyl fumarate. VUMERITY may be initiated the day following discontinuation of dimethyl fumarate <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .