Included as part of the "PRECAUTIONS" Section
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis
(NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these
patients unless the diagnostic information is essential and not available with non-contrast enhanced
MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic,
severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The
risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2)
and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF
may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any
diagnosis of NSF following MultiHance administration to Bracco Diagnostics (1-800-257-5181) or
FDA (1-800-FDA-1088 or www.fda.gov/medwatch).
Screen patients for acute kidney injury and other conditions that may reduce renal function.
Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease
in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced
kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in
the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age
>60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended
doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific
GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed
the recommended MultiHance dose and allow a sufficient period of time for elimination of the drug
prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt
initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast
agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
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 MultiHance administration and resolved with
prompt emergency treatment.
Prior to MultiHance administration, ensure the availability of personnel trained and medications to
treat hypersensitivity reactions. If such a reaction occurs stop MultiHance and immediately begin
appropriate therapy. Additionally, consider the risk for hypersensitivity reactions, especially in
patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders.
Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours
after MultiHance administration.
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. 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
Consequences of gadolinium retention in the brain have not been established. Pathologic and
clinical consequences of retention in skin and other organs have been established in patients with
impaired renal function [see Nephrogenic Systemic Fibrosis (NSF)]. 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 [see ADVERSE REACTIONS].
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.
Acute Renal Failure
In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function
have occurred with the use of gadolinium-based contrast agents. The risk of renal failure may
increase with increasing dose of the contrast agent. Screen all patients for renal dysfunction by
obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for
patients with a history of renal dysfunction.
Extravasation And Injection Site Reactions
Extravasation of MultiHance may lead to injection site reactions, characterized by local pain or
burning sensation, swelling, blistering, and necrosis. In animal experiments, local reactions
including eschar and necrosis were noted even on Day 8 post perivenous injection of MultiHance.
Exercise caution to avoid local extravasation during intravenous administration of MultiHance. If
extravasation occurs, evaluate and treat as necessary if local reactions develop.
Cardiac arrhythmias have been observed in patients receiving MultiHance in clinical trials [see ADVERSE REACTIONS]. Assess patients for underlying conditions or medications that predispose
A double-blind, placebo-controlled, 24-hour post dose continuous monitoring, crossover study in 47
subjects evaluated the effect of 0.2 mmol/kg MultiHance on ECG intervals, including QTc. The
average changes in QTc values compared with placebo were minimal (<5 msec). QTc prolongation
between 30 and 60 msec were noted in 20 subjects who received MultiHance vs. 11 subjects who
received placebo. Prolongations ≥61 msec were noted in 6 subjects who received MultiHance and
in 3 subjects who received placebo. None of these subjects had associated malignant arrhythmias.
The effects on QTc by MultiHance dose, other drugs, and medical conditions were not
Interference With Visualization Of Certain Lesions
Certain lesions seen on non-contrast images may not be seen on contrast- images. Exercise caution
when interpreting contrast MR images in the absence of companion non-contrast MR images.
Patient Counseling Information
Nephrogenic Systemic Fibrosis
Instruct patients to inform their physician if they:
- have a history of kidney and/or liver disease, or
- have recently received a GBCA.
GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel
patients at risk for NSF:
- Describe the clinical manifestations of NSF
- Describe procedures to screen for the detection of renal impairment.
Instruct the patients to contact their physician if they develop signs or symptoms of NSF
following MultiHance 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.
Common Adverse Reactions
Inform patients that they may experience:
- reactions along the venous injection site, such as mild and transient burning or pain or
feeling of warmth or coldness at the injection site
- side effects of feeling hot, nausea, and headache.
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].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of
The Results For MultiHance Were Negative In The Following Genetic Toxicity Studies
- in vitro bacteria reverse mutation assays,
- an in vitro gene mutation assay in mammalian cells,
- an in vitro chromosomal aberration assay,
- an in vitro unscheduled DNA synthesis assay, and
- an in vivo micronucleus assay in rats.
MultiHance had no effect on fertility and reproductive performance at IV doses of up to 2
mmol/kg/day (3 times the human dose on body surface basis) for 13 weeks in male rats and
for 32 days in female rats. However, vacuolation in testes and abnormal spermatogenic cells
were observed when MultiHance was intravenously administered to male rats at 3
mmol/kg/day (5 times the human dose on body surface basis) for 28 days. The effects were
not reversible following 28-day recovery period. The effects were not reported in dog and
monkey studies (at doses up to about 11 and 10 times the human dose on body surface basis
for dogs (28 days dosing) and monkeys (14 days dosing), respectively).
Use In Specific Populations
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
(see Data). 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%,
Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA
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) and mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium
concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months.
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. There
were no adverse effects on the birth, survival, growth, development and fertility of the F1 generation
at doses up to 2 mmol/kg in a rat peri- and post-natal (Segment III) study.
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.
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 [see Clinical Studies]. Adverse reactions in pediatric patients were similar to
those reported in adults [see ADVERSE REACTIONS]. No dose adjustment according to age is
necessary in pediatric patients [see DOSAGE AND ADMINISTRATION, Pharmacokinetics]. The
safety of MultiHance has not been established in preterm neonates.
Of the total number of 4967 adult subjects in clinical studies of MultiHance, 33% were 65 or
older. No overall differences in safety or effectiveness were observed between these elderly
subjects and the younger subjects.
The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
MultiHance may be greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function it may be useful to monitor renal function.