Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or
revisions underlined:
Risk Summary
. . .
Available data from a pregnancy registry for
dimethyl fumarate (the prodrug of BAFIERTAM), observational studies, and
pharmacovigilance with 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).
. . .
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and/or
revisions underlined:
Before taking and
while you take BAFIERTAM, tell your doctor about all of your medical
conditions, including if you:
.
. .
. . .
Approved Drug Label (PDF)
5
Warnings and Precautions
5.4 Lymphopenia
(Additions and/or revisions underlined)
BAFIERTAM may decrease lymphocyte counts. In the MS placebo-controlled
trials with dimethyl fumarate (the prodrug of BAFIERTAM), 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 <0.5x109/L (lower limit of
normal 0.91x109/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 <0.8x109/L or <0.5x109/L
in controlled trials, although one patient in an extension study developed PML
in the setting of prolonged lymphopenia (lymphocyte counts predominantly
<0.5x109/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 109/L for at
least six months); in this group of patients, the majority of lymphocyte counts remained <0.5x109/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:
weeks in patients with mild lymphopenia (lymphocyte count greater than or equal to 0.8x109/L) at discontinuation,
10.0 weeks
in patients with moderate lymphopenia (lymphocyte count 0.5 to <0.8x109/L) at
discontinuation, and
16.7 weeks in patients
with severe lymphopenia (lymphocyte count <0.5x109/L) at discontinuation.
...
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 BAFIERTAM during pregnancy. Pregnant women exposed to
BAFIERTAM and healthcare providers are encouraged to contact Banner Life
Sciences at 1-866-MMF-95MG (1-866-663- 9564).
...
8.4 Pediatric Use
(Additions and/or revisions underlined)
Safety and effectiveness in pediatric patients
have not been established.
Juvenile Animal Toxicity Data
Oral administration of monomethyl fumarate
(MMF) (0, 40, 100, or 250 mg/kg/day) to juvenile rats from
postnatal day 28 to 70 resulted in reduced body weight and bone growth, delayed
sexual maturation in females, and renal tubular (exfoliated cells or
degeneration) and gastrointestinal (nonglandular stomach hyperkeratosis or
hyperplasia) effects at all but the lowest dose tested. No adverse effects were
observed on neurobehavioral development.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
...
Pregnancy and Pregnancy Registry
Instruct
patients that if they are pregnant or plan to become pregnant
while taking BAFIERTAM they should inform their
healthcare provider. Advise patients that there is a pregnancy registry that
monitors pregnancy outcomes in women exposed to BAFIERTAM during pregnancy, and
they can be enrolled by calling 1-866-MMF-95MG (1-866-663-9564) [see Use
in Specific Populations (8.1)].
...
Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Serious Gastrointestinal Reactions
(Additions and/or revisions underlined)
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 dimethyl fumarate, 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 events 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 BAFIERTAM for new or worsening severe gastrointestinal signs and symptoms.
6
Adverse Reactions
(Additions and/or revisions underlined)
The following clinically significant adverse reactions
are described elsewhere
in the labeling:
Anaphylaxis and Angioedema [see
Warnings and Precautions (5.1)]
Progressive Multifocal Leukoencephalopathy [see Warnings
and Precautions (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). In clinical trials,
the incidence of GI events was higher early in the course of treatment
(primarily during the first month) 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 patients on placebo 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 (the prodrug of BAFIERTAM). 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)
…
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 BAFIERTAM 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)].
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The following adverse reactions have been
identified during post approval use of dimethyl fumarate (the prodrug of
BAFIERTAM). 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
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
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