Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

VUMERITY (NDA-211855)

(DIROXIMEL FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/22/2024 (SUPPL-15)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

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).

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Pregnancy and Pregnancy Registry

Instruct patients that if they are pregnant or plan to become pregnant while taking VUMERITY they should inform their healthcare provider.

Encourage patients to enroll in the VUMERITY Pregnancy Registry if they become pregnant while taking VUMERITY [see Use in Specific Populations (8.1)].

PATIENT INFORMATION

Additions and/or revisions underlined:

Before taking and while you take VUMERITY, tell your doctor about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. It is not known if VUMERITY will harm your unborn baby.
- If you become pregnant while taking VUMERITY, talk to your healthcare provider about enrolling in the VUMERITY Pregnancy Registry. You can enroll in this registry by calling 1-833-569-2635 or visiting www.vumeritypregnancyregistry.com. The purpose of this registry is to monitor the health of you and your baby.

12/13/2023 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Serious Gastrointestinal Reactions

(Newly added subsection)

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%) [see Adverse Reactions 6.1)].

Monitor patients, promptly evaluate, and discontinue VUMERITY for new or worsening severe gastrointestinal signs and symptoms.

6 Adverse Reactions

(Additions and/or revisions underlined)

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 (5.5)]
Flushing [see Warnings and Precautions (5.6)]
Serious Gastrointestinal Reactions [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

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%).

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have 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)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Flushing

Inform patients that flushing is one of 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. Advise patients experiencing flushing that taking VUMERITY with food (avoid high-fat, high-calorie meal or snack) or taking a non-enteric coated aspirin prior to taking VUMERITY may help [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Gastrointestinal (GI) Reactions

Inform patients that GI events (abdominal pain, diarrhea, and nausea) are some of the most common adverse reactions, especially at the initiation of therapy, and may decrease over time. Some patients may experience more severe GI events, Advise patients to immediately contact their healthcare provider and discontinue VUMERITY if they experience gastrointestinal bleeding (e.g., rectal bleeding, bloody diarrhea, hematemesis) or other serious gastrointestinal adverse events (e.g., severe abdominal pain, severe vomiting and/or diarrhea) [see Warnings and Precautions (5.7)].

…

02/10/2023 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Lymphopenia

Additions and/or revisions underlined:

…

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. 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 greater than or equal to 0.8 × 109/L) at discontinuation,
10.0 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to <0.8 × 109/L) at discontinuation, and

16.7 weeks in patients with severe lymphopenia (lymphocyte count <0.5 × 109/L) at discontinuation.

…

09/29/2022 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

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.

…

6.2 Postmarketing Experience

Additions and/or revisions underlined

…

Gastrointestinal Disorders: Acute pancreatitis

…

02/10/2022 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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.

Hepatobiliary Disorders: Liver function abnormalities (elevations in transaminases greater than or equal to 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

01/29/2021 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added information)

Rhinorrhea has been reported with dimethyl fumarate in post marketing experience.

08/21/2020 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Progressive Multifocal Leukoencephalopathy

Additions and/or revisions underlined:

… PML has also occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9 × 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 …

Newly added subsection:

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 [see Adverse Reactions (6.2)].

6 Adverse Reactions

Newly added to bulleted line listing:

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

6.2 Postmarketing Experience

Newly added information:

Herpes zoster infection and other serious opportunistic infections have been reported with dimethyl fumarate administration in postmarketing experience [see Warnings and Precautions (5.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

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 associated with herpes zoster or other serious opportunistic infections [see Warnings and Precautions (5.3)].

PATIENT INFORMATION

Additions and/or revisions underlined:

What are the possible side effects of VUMERITY?

VUMERITY may cause serious side effects including:

herpes zoster infections (shingles), including central nervous system infections.