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. ProHance
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 ProHance have not been established with
intrathecal use. ProHance 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 PROHANCE?
GBCAs like
PROHANCE 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 PROHANCE is safe and effective with intrathecal use.
PROHANCE is not approved for this use.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Hypersensitivity Reactions
(Additions and/or
revisions underlined)
Anaphylactic
and anaphylactoid reactions have been reported, involving cardiovascular, respiratory,
and/or cutaneous manifestations. Some patients experienced circulatory collapse
and died. In most cases, initial symptoms occurred within minutes of ProHance administration
and resolved with prompt emergency treatment.
Prior
to ProHance administration, ensure the availability of trained personnel and medications
to treat hypersensitivity reactions. Consider the risk for hypersensitivity reactions,
especially in patients with a history of hypersensitivity reactions or
a history of asthma or other allergic disorders. If such a
reaction occurs, stop ProHance and immediately begin appropriate therapy. Observe
patients for signs and symptoms of a hypersensitivity reaction during and for up
to 2 hours after ProHance administration.
6
Adverse Reactions
(Additions and/or revisions
underlined)
The
following serious adverse reactions are discussed in greater detail in other
sections of the prescribing information:
6.1 Clinical Trials Experience
(Extensive
changes; please refer to label)
6.2 Postmarketing Experience
(Extensive
changes; please refer to label)
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions
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).
Because
of the potential risks of gadolinium to the fetus, use ProHance only if imaging
is essential during pregnancy and cannot be delayed.
In
animal reproduction studies in rats, gadoteridol doubled the incidence of post-implantation
loss at up to 16 times the recommended human dose (RHD). There were no adverse developmental
effects observed in rabbits with intravenous administration of gadoteridol during
organogenesis at doses up to 19 times the recommended human dose of 0.1 mmol/kg
(see Data).
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
agent 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.
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
Gadoteridol
was administered in intravenous doses of 0, 0.375, 1.5, 6.0, and 10 mmol/kg/day
[0.6, 2.4, 9.7, and 16 times the recommended human dose (RHD) based
on body surface area (BSA)] to female rats from gestational day (GD)6 until GD17.
Gadoteridol at 10 mmol/kg/day for 12 days during gestation doubled the incidence
of post-implantation loss. When rats were administered 6.0 or 10.0 mmol/kg/day
for 12 days, an increase in spontaneous locomotor activity was observed in the offspring.
Pregnant rabbits were administered gadoteridol in intravenous doses of 0, 0.4,
1.5, and 6 mmol/kg/day (1.3, 4.8, and 19.4 times the RHD based on BSA) from GD6
to GD18. Gadoteridol increased the incidence of spontaneous abortion and early
delivery in rabbits administered 6 mmol/kg/day for 13 days during gestation.
8.2 Lactation
(Newly added subsection)
Risk
Summary
There
are no data on the presence of gadoteridol 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 and there is limited GBCA gastrointestinal absorption in the breast-fed
infant. Gadoteridol is present in rat milk (see Data). The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for ProHance and any potential adverse effects on the breastfed infant from
ProHance or from the underlying maternal condition.
Data
ProHance
excretion in the milk of lactating rats was evaluated at 30 minutes, 6 and 24 hours
after intravenous administration of 0.1 mmol/kg of 153Gd-gadoteridol to nursing
mothers. Small amounts of compound were found in milk immediately after injection
(0.14% of the ID), with the amount declining to a low level 24 hours after injection
(<0.01% of the ID).
8.4 Pediatric Use
(Additions and/or revisions
underlined)
The
safety and effectiveness of ProHance have been established for use with MRI 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 17 years of age. Pediatric use is based on evidence of effectiveness in adults
and in 103 pediatric patients 2 years of age and older, in addition to experience
in 125 pediatric patients birth to less than 2 years of age that supported extrapolation
from adult data [see Clinical Studies (14)].
Adverse reactions in pediatric patients were similar to those reported in adults
[see Adverse Reactions (6.1)].
The
safety and efficacy of > 0.1 mmol/kg, and sequential and/or repeat procedures have
not been studied in pediatric patients [see
Indications and Usage (1) and Dosage and Administration (2)].
No
case of NSF associated with ProHance or any other GBCA has been identified in pediatric
patients ages 6 years and younger. Pharmacokinetic studies suggest that weight normalized
clearance of ProHance is similar in pediatric patients and adults, including pediatric
patients age younger than 2 years. Normal estimated GFR (eGFR) is around 30 mL/min/1.73m2
at birth and increases to mature levels around 1 year of age, reflecting growth
in both glomerular function and relative body surface area. Clinical studies in
pediatric patients younger than 1 year of age have been conducted in patients with
the following minimum eGRF; 59.37 mL/min/1.73m2 (age just after birth to < 30
days), 118.84 mL/min/1.73m2 (age 30 days to < 6 months), 140.44 mL/min/1.73m2
(age 6 to 12 months).
8.6 Renal Impairment
(Newly added subsection)
No
ProHance dosage adjustment is recommended for patients with renal impairment. Gadoteridol
can be removed from the body by hemodialysis [see Warning and Precautions (5.1) and Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or revisions
underlined)
Medication
Guide
Nephrogenic
Systemic Fibrosis
Instruct
patients to inform their physician if they:
GBCAs
increase the risk for NSF in patients with impaired elimination of the drugs. To
counsel patients at risk for NSF:
Instruct
patients to contact their physician if they develop signs or symptoms of NSF following
ProHance administration, such as burning, itching, swelling, scaling, hardening
and tightening of the skin; red or dark patches on the skin; stiffness in joints
with trouble moving, bending or straightening the arms, hands, legs or feet; pain
in the hip bones or ribs; or muscle weakness.
General
Precautions
Pregnancy: Advise a pregnant woman of the potential risk
of fetal exposure to ProHance [see
Use in Specific Populations (8.1)
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 [see Warnings and Precautions
(5.3)].
Approved Drug Label (PDF)
5
Warnings and Precautions
WARNINGS
(Newly Added Subsection)
Gadolinium Retention
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.
PRECAUTIONS
(Additions and/or
revisions are underlined)
Nephrogenic Systemic Fibrosis: GBCAs increase the risk for
NSF among patients with impaired elimination of the drugs. To counsel patients at
risk for NSF…
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.
6
Adverse Reactions
(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 and Appendages: Gadolinium
associated plaques
8
Use in Specific Populations
Pregnancy
(Additions and/or
revisions are underlined)
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. Because of the potential risks of gadolinium
to the fetus, use ProHance only if imaging is essential during pregnancy and cannot
be delayed.
Contrast enhancement is visualized in the human 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.
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)
Medication Guide
(Newly added Medication Guide; please refer to
labeling)
Get Email Alerts |
Guide
