Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Hypersensitivity Reactions
Additions and/or revisions underlined:
Anaphylactic and other hypersensitivity reactions
with cardiovascular, respiratory and cutaneous manifestations, ranging from
mild to severe, including shock have occurred following EOVIST administration.
Most hypersensitivity reactions to EOVIST have occurred within half an hour
after administration. Delayed reactions can occur up to several days after
EOVIST administration [see Adverse
Reactions (6.2)].
…
5.6 Extravasation and Injection Site Reactions
Additions
and/or revisions underlined:
Injection
site reactions such as pain have been reported in clinical studies with EOVIST [see Adverse Reactions (6.1)]. Extravasation into tissues during EOVIST
administration may result in local tissue reactions such as myocyte necrosis
and inflammation [see Nonclinical Toxicology (13.2)]. Ensure catheter and venous patency before the
injection of EOVIST.
5.7 Interference with Laboratory Tests
Additions
and/or revisions underlined:
EOVIST
can interfere with serum iron determination using complexometric methods (for
example, ferrocene complexation
method) [see Drug Interactions (7)].
6
Adverse Reactions
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
…
Adverse Reactions in Pediatric Patients
In a study of
EOVIST in 52 pediatric patients between 2 months of age and 18 years of age, no
new safety signals were observed [see Use in Specific Populations (8.4)].
6.2 Postmarketing
Experience
Additions
and/or revisions underlined:
…
Renal Disorders: Nephrogenic
systemic fibrosis
…
7
Drug Interactions
Newly
added section:
Serum
Iron Test
EOVIST
contains caloxetate trisodium that can interfere with serum iron determination
using complexometric methods (for example, ferrocene complexation method) and
may result in falsely high or low values for up to 24 hours after the
administration of EOVIST. Conduct serum iron tests either before or at least 24
hours following administration of EOVIST.
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
GBCAs cross the placenta and result in fetal
exposure. In human placental imaging studies, contrast was visualized in the
placenta and fetal tissues after maternal GBCA administration. Based on animal
studies, use of GBCAs during pregnancy may result in fetal gadolinium
retention.
Published epidemiological studies on the association between GBCAs and adverse fetal outcomes have
reported inconsistent findings and have important methodological
limitations (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% to 4% and 15% to
20%, respectively.
Data
Human Data
Available data regarding exposure to GBCAs during pregnancy from published epidemiological
studies are not sufficient to assess the risk of adverse fetal and
neonatal effects that may be associated with GBCAs. A retrospective cohort
study of over 1.4 million pregnancies in Ontario, Canada, comparing pregnant
women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher
occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI.
Limitations of this study include a lack of comparison with non-contrast MRI
and lack of information about the maternal indication for MRI. Another
retrospective cohort study of over 11 million pregnancies in the Medicaid
database found no increased risk of fetal or neonatal death or Neonatal
Intensive Care Unit admission when comparing pregnancies exposed to GBCA MRI
versus non-contrast MRI. These two retrospective studies assessed a limited
number of potential pregnancy outcomes and did not evaluate the full spectrum
of potential fetal risk.
…
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness
of EOVIST for magnetic resonance imaging (MRI) of the liver to detect
and characterize lesions have been established in pediatric patients, including
term neonates. Use of EOVIST in this age group is supported by evidence from
adequate and well-controlled studies in adults and an observational study
in 52 pediatric patients between 2 months of age and 18 years of
age who were referred for evaluation of suspected or known focal liver
lesions. In this observational study, EOVIST improved border delineation and
increased contrast of the primary lesion in the majority of patients when
compared to non-contrast images [see
Adverse Reactions (6.1) and Clinical Studies (14)].
The safety and effectiveness of EOVIST have not been
established in preterm neonates.
8.6 Renal Impairment
Additions
and/or revisions underlined:
In
patients with renal impairment, the exposure of gadoxetate is increased
compared to patients with normal renal function.
This may increase
the risk of adverse reactions such as nephrogenic systemic fibrosis (NSF). EOVIST
can be removed by hemodialysis [see
Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
In
patients with end-stage renal failure, hepatic contrast was reduced,
which was attributed to significantly elevated serum ferritin levels [see Dosage and Administration (2.3) and
Warnings and Precautions (5.8)].
In
patients with moderate renal impairment, hepatic contrast did not differ among
the groups.
8.7 Hepatic Impairment
Additions
and/or revisions underlined:
In
patients with severe hepatic impairment, the exposure of gadoxetate is
increased and EOVIST imaging performance may be impaired [see Dosage and Administration (2.3), Warnings and Precautions (5.8), and Clinical Pharmacology (12.3)].
In
patients with mild or moderate hepatic impairment, the exposure of
gadoxetate was moderately increased compared to healthy subjects
with normal liver function, but hepatic contrast signal did not differ
among the groups.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
…
Nephrogenic
Systemic Fibrosis
Inform
the patient that EOVIST may increase the risk for NSF among patients with
impaired elimination of the drug and that NSF may result in fatal or
debilitating fibrosis affecting the skin, muscle, and internal organs.
…
Pregnancy
Advise
pregnant women of the potential risk of fetal exposure to EOVIST [see Use in Specific Populations (8.1)].
Approved Drug Label (PDF)
Boxed Warning
Additions and revisions underlined:
WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and
NEPHROGENIC SYSTEMIC FIBROSIS
See full prescribing information for complete boxed warning.
• Intrathecal administration of gadolinium-based contrast
agents
(GBCAs) can cause serious adverse reactions including
death,
coma, encephalopathy, and seizures. EOVIST is not
approved for
intrathecal use (5.1)
. . .
5
Warnings and Precautions
5.1 Risk Associated with Intrathecal Use
Newly added subsection:
Intrathecal administration of GBCAs
can cause serious adverse reactions including death, coma, encephalopathy, and
seizures. The safety and effectiveness of EOVIST have not been established with intrathecal use. EOVIST is not approved for intrathecal use [see Dosage and Administration (2.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
Additions and revisions underlined:
.
. .
What is the most important information I should know about Eovist?
GBCAs like EOVIST may cause serious
side effects including
death, coma, encephalopathy, and seizures when it
is given intrathecally (injection given into the spinal canal). It is not known
if EOVIST is safe and effective with intrathecal use. EOVIST is not approved
for this use.
.
. .
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Gadolinium Retention
(Newly Added Subsection)
Gadolinium is retained for months or
years in several organs. The highest concentrations (nanomoles per gram of
tissue) have been identified in the bone, followed by other organs (for
example, brain, skin, kidney, liver, and spleen). The duration of retention
also varies by tissue and is longest in bone. Linear GBCAs cause more retention
than macrocyclic GBCAs. At equivalent doses, gadolinium retention varies among
the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide)
causing greater retention than other linear agents [Eovist (gadoxetate
disodium), Magnevist (gadopentetate dimeglumine),MultiHance (gadobenate
dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs
[Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance
(gadoteridol)].
Consequences of gadolinium retention in
the brain have not been established. Pathologic and clinical consequences of
GBCA administration and retention in skin and other organs have been
established in patients with impaired renal function. There are rare reports of
pathologic skin changes in patients with normal renal function. Adverse events
involving multiple organ systems have been reported in patients with normal
renal function without an established causal link to gadolinium retention.
While clinical consequences of
gadolinium retention have not been established in patients with normal renal
function, certain patients might be at higher risk. These include patients
requiring multiple lifetime doses, pregnant and pediatric patients, and
patients with inflammatory conditions. Consider the retention characteristics
of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA
imaging studies particularly closely spaced studies, when possible.
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions
and/or revisions are underlined)
General
Disorders and Administration Site Conditions:
Adverse events with variable onset and duration have been reported after
GBCA administration. These include fatigue, asthenia, pain syndromes, and
heterogeneous clusters of symptoms in the neurological, cutaneous, and
musculoskeletal systems.
Skin: Gadolinium
associated plaques
8
Use in Specific Populations
8.1 Pregnancy
(Additions
and/or revisions are underlined)
GBCAs have been shown to cross the
human placenta and result in fetal exposure and gadolinium retention. The human
data on the association between GBCAs and adverse fetal outcomes are limited
and inconclusive (see Data). In animal reproduction studies,The background risk in the U.S. general population of
major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized
pregnancies. no teratogenicity was observed with repeated daily intravenous
administration of gadoxetate disodium to rats during organogenesis at doses up
to 32 times the recommended single human dose; however, an increase in
preimplantation loss was noted at doses 3.2 times the single human dose. Post
implantation loss was observed with repeated daily intravenous administration
of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26
times the recommended single human dose. Because
of the potential risks of gadolinium to the fetus, use
EOVIST only if imaging is essential during pregnancy and cannot be delayed.
Data
Human Data
Contrast enhancement is visualized in
the placenta and fetal tissues after maternal GBCA administration.
Cohort studies and case reports on
exposure to GBCAs during pregnancy have not reported a clear association
between GBCAs and adverse effects in the exposed neonates. However, a
retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant
women who did not have an MRI, reported a higher occurrence of stillbirths and
neonatal deaths in the group receiving GBCA MRI. Limitations of this study
include a lack of comparison with non- contrast MRI and lack of information
about the maternal indication for MRI. Overall, these data preclude a reliable
evaluation of the potential risk of adverse fetal outcomes with the use of
GBCAs in pregnancy.
Animal Data
Gadolinium Retention
GBCAs administered to pregnant
non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in
measurable gadolinium concentration in the offspring in bone, brain, skin,
liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant
mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable
gadolinium concentrations in the pups in bone, brain, kidney, liver, blood,
muscle, and spleen at one month postnatal age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
Advise the
patient to read the FDA-approved patient labeling (Medication Guide).
General Precautions
Gadolinium Retention
• Advise
patients that gadolinium is retained for months or years in brain, bone, skin,
and other organs in patients with normal renal function. The clinical
consequences of retention are unknown. Retention depends on multiple factors
and is greater following administration of linear GBCAs than following
administration of macrocyclic GBCAs.
Medication Guide
(Newly added
Medication Guide; please refer to labeling)
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