Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined:
![]()
WARNING: RISK ASSOCIATED WITH
INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS
Risk Associated
with Intrathecal Use
Intrathecal
administration of gadolinium-based contrast agents (GBCAs) can cause serious
adverse reactions including death, coma, encephalopathy, and seizures.
MultiHance is not approved for intrathecal use [see Warnings and Precautions (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 MultiHance have not been established with
intrathecal use. MultiHance is not approved for intrathecal use [see Dosage
and Administration (2.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined:
…
What
is the most important information I should know about MULTIHANCE?
• GBCAs like MULTIHANCE may cause serious side
effects including death, coma, encephalopathy, and seizures when it is given
intrathecally (injection given into the spinal cord). It is not known if
MULTIHANCE is safe and effective with intrathecal use. MULTIHANCE 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 (e.g. 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 Post-Marketing Experience
(Additions and/or revisions are underlined)
Immune
System Disorders:
Anaphylactic, anaphylactoid and hypersensitivity reactions manifested with
various degrees of severity up to anaphylactic shock, loss of consciousness and
death…
General
Disorders and Administration Site Conditions:
Extravasation of MultiHance may lead to injection site reactions, characterized
by local pain or burning sensation, swelling, blistering, and necrosis.
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
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are
underlined)
Risk Summary
GBCAs cross the 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, gadobenate dimeglumine has been shown to be teratogenic in rabbits
following repeated intravenous administration during organogenesis at doses up
to 6 times the recommended human dose. There were no adverse developmental
effects observed in rats with intravenous administration of gadobenate
dimeglumine during organogenesis at doses up to three times the recommended
human dose. Because of the potential
risks of gadolinium to the fetus, use MultiHance only if imaging is essential
and cannot be delayed.
The estimated 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 is
15 to 20%, respectively.
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.
Reproductive Toxicology
Gadobenate dimeglumine has been shown
to be teratogenic in rabbits when administered intravenously at 2 mmol/kg/day
(6 times the recommended human dose
based on body surface area) during organogenesis (day 6 to 18) inducing
microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate
litters. In addition, MultiHance administered intravenously at 3
mmol/kg/day (10 times the recommended human dose based on body surface
area) has been shown to increase intrauterine deaths in rabbits. There was no
evidence that MultiHance induced teratogenic effects in rats at doses up to 2
mmol/kg/day (3 times the recommended human dose based on body surface
area), however, rat dams exhibited no systemic toxicity at this dose…
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions
and/or revisions are underlined)
Risk Summary
Limited literature reports that
breastfeeding after gadobenate dimeglumine administration to the mother would result
in the infant receiving an oral dose of 0.001%-0.04% of the maternal dose. There
is no information on the effects of the drug on the breastfed infant or the effects
of the drug on milk production. Additionally, there is limited GBCA gastrointestinal
absorption. The developmental and health benefits of breastfeeding should be considered
together with the mother’s clinical need for MultiHance and any potential adverse
effects on the breastfed infant from MultiHance or from the underlying maternal
condition.
8.4 Pediatric Use
(Additions
and/or revisions are underlined)
MultiHance is approved for
intravenous use for MRI of the CNS to visualize lesions with abnormal blood
brain barrier or abnormal vascularity of the brain, spine, and associated
tissues in pediatric patients from birth, including term neonates, to less than
17 years of age. Pediatric use is based
on evidence of effectiveness in adults and in 202 pediatric patients 2 years of
age and older, in addition to experience in 105 pediatric patients birth to
less than 2 years of age that supported extrapolation from adult data. Adverse
reactions in pediatric patients were similar to those reported in adults. No dose adjustment according to age is
necessary in pediatric patients two years of age and older. For pediatric
patients, less than 2 years of age, the recommended dosage range is 0.1 to 0.2
mL/kg. The safety of MultiHance has not been established in preterm neonates.
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).
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)
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 (e.g. 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 Post-Marketing Experience
(Additions and/or revisions are underlined)
Immune
System Disorders:
Anaphylactic, anaphylactoid and hypersensitivity reactions manifested with
various degrees of severity up to anaphylactic shock, loss of consciousness and
death…
General
Disorders and Administration Site Conditions:
Extravasation of MultiHance may lead to injection site reactions, characterized
by local pain or burning sensation, swelling, blistering, and necrosis.
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
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are
underlined)
Risk Summary
GBCAs cross the 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, gadobenate dimeglumine has been shown to be teratogenic in rabbits
following repeated intravenous administration during organogenesis at doses up
to 6 times the recommended human dose. There were no adverse developmental
effects observed in rats with intravenous administration of gadobenate
dimeglumine during organogenesis at doses up to three times the recommended
human dose. Because of the potential
risks of gadolinium to the fetus, use MultiHance only if imaging is essential
and cannot be delayed.
The estimated 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 is
15 to 20%, respectively.
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.
Reproductive Toxicology
Gadobenate dimeglumine has been shown
to be teratogenic in rabbits when administered intravenously at 2 mmol/kg/day
(6 times the recommended human dose
based on body surface area) during organogenesis (day 6 to 18) inducing
microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate
litters. In addition, MultiHance administered intravenously at 3
mmol/kg/day (10 times the recommended human dose based on body surface
area) has been shown to increase intrauterine deaths in rabbits. There was no
evidence that MultiHance induced teratogenic effects in rats at doses up to 2
mmol/kg/day (3 times the recommended human dose based on body surface
area), however, rat dams exhibited no systemic toxicity at this dose…
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions
and/or revisions are underlined)
Risk Summary
Limited literature reports that
breastfeeding after gadobenate dimeglumine administration to the mother would result
in the infant receiving an oral dose of 0.001%-0.04% of the maternal dose. There
is no information on the effects of the drug on the breastfed infant or the effects
of the drug on milk production. Additionally, there is limited GBCA gastrointestinal
absorption. The developmental and health benefits of breastfeeding should be considered
together with the mother’s clinical need for MultiHance and any potential adverse
effects on the breastfed infant from MultiHance or from the underlying maternal
condition.
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).
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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