Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined:
WARNING:
RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS
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Risk
Associated with Intrathecal Use
Intrathecal
administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse
reactions including death, coma, encephalopathy, and seizures. DOTAREM 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 DOTAREM have not
been established with intrathecal use.
DOTAREM
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 DOTAREM?
GBCAs like DOTAREM 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 DOTAREM is safe and
effective with intrathecal use. DOTAREM 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.
8
Use in Specific Populations
8.1 Pregnancy
(Additions
and/or revisions are underlined)
Risk
Summary
GBCAs 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. In animal reproduction
studies, there were no adverse developmental effects observed in rats or
rabbits with intravenous administration of gadoterate megulmine during organogenesis
at doses up to 16 and 10 times, respectively, the recommended human dose. Because
of the potential risks of gadolinium to the fetus, use
DOTAREM 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 material 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)
17.3 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)
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions and revisions underlined)
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the 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 below reflect DOTAREM exposure in
2867 patients, representing 2682 adults and 185 pediatric
patients. Overall, 55% of the patients were men. In clinical trials where
ethnicity was recorded, the ethnic distribution was 81% Caucasian, 11%
Asian, 4% Black, and 4% others. The average age was 53 years (range from <
1 week to 97 years).
Overall, 4% of patients reported at least one
adverse reaction, primarily occurring immediately or within 24 hours following
DOTAREM administration. Most adverse reactions were mild or moderate in
severity and transient in nature.
Table 2 lists adverse reactions that occurred in ?
0.2% patients who received DOTAREM.
(please refer to label to view Table 2)
Adverse reactions that occurred with a frequency
< 0.2% in patients who received DOTAREM include: feeling cold, feeling
hot, burning sensation, somnolence, pain, dizziness, dysgeusia, blood
creatinine increased, hypotension, hypertension, asthenia, fatigue,
injection site reactions (inflammation, extravasation, pruritus, swelling, warmth),
paraesthesia, pruritus, laryngeal discomfort, pain in extremity, vomiting,
anxiety and palpitations.
Adverse
Reactions in Pediatric Patients
During clinical trials, 185 pediatric
patients (52 aged < 24 months, 33 aged 2 - 5 years, 57 aged 6
- 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 7 pediatric
patients (3.8%) reported at least one adverse reaction following DOTAREM
administration. The most frequently reported adverse reaction was headache (1.1%).
Most adverse events were mild in intensity and
transient in nature.
8
Use in Specific Populations
8.1 Pregnancy
(subsection revised)
Risk Summary
There are no available data with DOTAREM use in
pregnant women to inform a drug-associated risk of adverse developmental
outcomes. While it is unknown if gadoterate crosses the placenta, other GBCAs
have been shown to cross the human placenta and result in fetal exposure. In
animal reproduction studies, there were no adverse developmental effects
observed in rats or rabbits with intravenous administration of gadoterate
meglumine during organogenesis at doses up to 16 and 10 times, respectively,
the recommended human dose (see Data). Advise pregnant women of the
potential risk of fetal exposure to GBCAs.
The estimated background risk of major birth defects
and miscarriage for the indicated population(s) are 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
Animal Data
Gadoterate meglumine was administered in intravenous
doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times the recommended human
dose (RHD) based on body surface area (BSA)] to female rats for 14 days before
mating, throughout the mating period and until gestation day (GD) 17. Pregnant
rabbits were administered gadoterate meglumine in intravenous doses of 0, 1, 3
and 7 mmol/kg/day (3, 10 and 23 times the RHD based on BSA) from GD6 to GD19.
No effects on embryo-fetal development were observed at doses up to
10 mmol/kg/day in rats and 3 mmol/kg/day in rabbits.
Maternal toxicity was observed in rats at
10 mmol/kg/day and in rabbits at 7 mmol/kg/day. This
maternal toxicity was characterized in rats by a slightly lower litter size and
gravid uterus weight compared to the control group, and in rabbits by a
reduction in body weight and food consumption.
8.2 Lactation
(subsection revised)
Risk Summary
There are no data on the presence of gadoterate in
human milk, the effects on the breastfed infant, or the effects on milk
production. However, published lactation data on other GBCAs indicate that 0.01
to 0.04% of the maternal gadolinium dose is present in breast milk.
Additionally, there is limited GBCA gastrointestinal absorption in the
breast-fed infant. Gadoterate is present in goat milk (see Data). The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for DOTAREM and any
potential adverse effects on the breastfed infant from DOTAREM or from the
underlying maternal condition.
Data
Nonclinical data demonstrate that gadoterate is
detected in goat milk in amounts < 0.1% of the dose intravenously
administered. Furthermore, in rats, absorption of gadoterate via the
gastrointestinal tract is poor (1.2% of the administered dose was absorbed and
eliminated in urine).
8.4 Pediatric Use
(subsection revised, additions
underlined)
The safety and efficacy of DOTAREM at a single dose
of 0.1 mmol/kg have been established in pediatric patients from birth (term
neonates ? 37 week gestational age) to 17 years of age based on clinical
data in 133 pediatric patients 2 years of age and older, and clinical data in
52 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 dosage adjustment according to age
is necessary in pediatric patients. The
safety of DOTAREM has not been established in preterm neonates.
No cases of NSF associated with DOTAREM or any other
GBCA have been identified in
pediatric patients age 6 years younger. Normal estimated GFR (eGFR)
is approximately 30 mL/minute/1.73m2 at birth and increases to adult values by
2 years of age.
Juvenile
Animal Data
Single and repeat-dose toxicity studies in neonatal
and juvenile rats did not reveal findings suggestive of a specific risk for use
in pediatric patients including term neonates and infants.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
17.3 General Precautions
(addition underlined)
Pregnancy: Advise pregnant women of the potential
risk of fetal exposure to gadoterate
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