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Diroximel fumarate

Vumerity

231MG capsule, delayed releaseVereinigte StaatenIm HandelZugelassen am 29. Okt. 2019

Inhalt auf Englisch

Anwendungsgebiete

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 )

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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 )

Warnhinweise und Vorsichtsmaßnahmen

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

Zwei Arzneimittel in einer Frage?

Nenn zwei oder mehr Arzneimittel und Osler führt einen Wechselwirkungscheck durch. Eine schwere Wechselwirkung steht ganz oben in der Antwort.

Osler entdecken

Diroximel fumarate

Vumerity

231MG capsule, delayed releaseVereinigte StaatenIm HandelZugelassen am 29. Okt. 2019

Inhalt auf Englisch

Im Register öffnenFrag Osler dazu

Anwendungsgebiete

Gegenanzeigen

Warnhinweise und Vorsichtsmaßnahmen

5.1

Zwei Arzneimittel in einer Frage?

Nenn zwei oder mehr Arzneimittel und Osler führt einen Wechselwirkungscheck durch. Eine schwere Wechselwirkung steht ganz oben in der Antwort.

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5.2Progressive 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 <0.5 × 10 9 /L for 3.5 years) while taking dimethyl fumarate [see Warnings and Precautions ( 5.4 )]. 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 (<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 <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.

5.4Lymphopenia

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 <1% of placebo patients experienced lymphocyte counts <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 <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 <0.5 × 10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] .

In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced prolonged, severe lymphopenia, (defined as lymphocyte counts <0.5 x 10 9 /L for at least six months); in this group of patients, the majority of lymphocyte counts remained <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 <0.8 x 10 9 /L) at discontinuation, and 16.7 weeks in patients with severe lymphopenia (lymphocyte count <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 treatmen

Schwangerschaft und Stillzeit

8.1Pregnancy Pregnancy Exposure Registry

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.vumeritypregnancyregistry.com. Risk Summary There are no adequate data on the developmental risk associated with the use of VUMERITY in pregnant women. Available data from a pregnancy registry for dimethyl fumarate (which has the same active metabolite as VUMERITY), observational studies, and pharmacovigilance pertaining to dimethyl fumarate use in pregnant women have not indicated an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Most of the reported exposures to dimethyl fumarate occurred during the first trimester of pregnancy (see Data ). In animal studies, administration of diroximel fumarate during pregnancy or throughout pregnancy and lactation resulted in adverse effects on embryofetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposures [ see Data ].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data In a prospective observational pregnancy registry for dimethyl fumarate (2013-2022), the rate of major birth defects among 362 live births and stillbirths from women who were exposed to dimethyl fumarate during pregnancy was 3.6% (95% CI: 1.9-6.1).

No specific pattern of major birth defects was identified. Important potential study limitations include exposure misclassification, no adjustment for confounders, and lack of an internal comparator cohort. Animal Data Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/day) to pregnant rats throughout organogenesis resulted in a decrease in fetal body weight and an increase in fetal skeletal variations at the highest dose tested, which was associated with maternal toxicity.

Plasma exposures (AUC) for MMF and HES (the major circulating drug-related compound in humans) at the no-effect dose (100 mg/kg/day) for adverse effects on embryofetal development were approximately 2 times those in humans at the recommended human dose (RHD) of 924 mg/day. Oral administration of diroximel fumarate (0, 50, 150, or 350 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in an increase in fetal skeletal malformations at the mid and high doses and reduced fetal body weight and increases in embryofetal death and fetal skeletal variations at the highest dose tested.

The high dose was associated with maternal toxicity. Plasma exposures (AUC) for MMF and HES at the no-effect dose (50 mg/kg/day) for adverse effects on embryofetal development were similar to (MMF) or less than (HES) those in humans at the RHD. Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/day) to rats throughout gestation and lactation resulted in reduced weight, which persisted into adulthood, and adverse effects on neurobehavioral function in offspring at the highest dose tested.

Plasma exposures (AUC) for MMF and HES at the no-effect dose for adverse effects on postnatal development (100 mg/kg/day) were approximately 3 times (MMF) or similar to (HES) those in humans at the RHD.

Nebenwirkungen

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.

6.1Clinical 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.

6.2Postmarketing 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

Vumerity

Anwendungsgebiete

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Warnhinweise und Vorsichtsmaßnahmen

5.1

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Vumerity

Anwendungsgebiete

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Warnhinweise und Vorsichtsmaßnahmen

5.1

Zwei Arzneimittel in einer Frage?

5.2Progressive Multifocal Leukoencephalopathy

5.3Herpes Zoster and Other Serious Opportunistic Infections

5.4Lymphopenia

Wechselwirkungen

7.1Concomitant Dimethyl Fumarate

Schwangerschaft und Stillzeit

8.1Pregnancy Pregnancy Exposure Registry

Nebenwirkungen

6.1Clinical Trials Experience

6.2Postmarketing Experience

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