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Product Label Table of Contents
Warning: Nephrogenic Systemic Fibrosis
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.
- The risk for NSF appears highest among patients with:
- chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or
- acute kidney injury.
- Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
- 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 from the body prior to re-administration. [see Warnings and Precautions (5.1)]
1.1 Mri Of The Central Nervous System (Cns)
MultiHance is indicated
for intravenous use in magnetic resonance imaging (MRI) of the central
nervous system (CNS) in adults and pediatric patients (including term
neonates), to visualize lesions with abnormal blood-brain barrier
or abnormal vascularity of the brain, spine, and associated tissues.
1.2 Mra Of Renal And Aorto-Ilio-Femoral Vessels
MultiHance is indicated for use in magnetic
resonance angiography (MRA) to evaluate adults with known or suspected
renal or aorto-ilio-femoral occlusive vascular disease.
2.1.1 Mri Of The Cns
In adults and in pediatric patients over
2 years of age, the recommended dose of MultiHance for MRI of the
CNS is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid bolus intravenous
injection. In pediatric patients below 2 years of age, the recommended
dosage range is 0.1 to 0.2 mL/kg administered as a rapid bolus intravenous
injection. To ensure complete injection of the contrast medium, follow
the injection with a saline flush of at least 5 mL. Imaging of the
CNS can be performed starting immediately after the bolus injection
2.1.2 Mra Of Renal And Aorto-Ilio-Femoral Vessels
For MRA examination, the recommended dose
is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid bolus intravenous
injection followed by at least 20 mL saline flush either manually
or using an automatic injector system. Start imaging immediately after
the administration of MultiHance, with scan delay calculated by test
bolus or automatic bolus detection technique. If an automatic contrast
detection pulse sequence is not used for bolus timing, then a test
bolus injection of 1-2 mL of MultiHance should be used to calculate
the appropriate scan delay.
2.2 Dosing Table
|*For pediatric patients
less than 2 years of age, one-half of the per kg dose may be used.|
|TABLE 1: WEIGHT-BASED DOSING VOLUMES FOR:|
(ADULTS AND PEDIATRICS ≥2 YEARS OF AGE*)
MRA IMAGING (ADULTS ONLY)
| || ||0.1mM/kg dose|
|Kilograms (Kg)||Pounds (lb)||Volume, Milliliters
Inspect the MultiHance vial visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Draw MultiHance into a syringe and inject using sterile technique.
Do not mix intravenous medications or parenteral nutrition solutions with MultiHance. Do not administer other medications in the same intravenous line with MultiHance.
MultiHance vials are intended for single use only. Administer immediately after opening and discard any unused product.
3 Dosage Forms And Strengths
MultiHance is a sterile, nonpyrogenic, clear, colorless to slightly yellow aqueous solution for intravenous use only, containing 529 mg gadobenate dimeglumine per mL.
MultiHance is contraindicated in patients with known allergic or hypersensitivity reactions to gadolinium-based contrast agents [see Warnings and Precautions (5.2)].
5.1 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 (2) and Clinical Pharmacology (12)].
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
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.
5.3 Gadolinium Retention
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 [see Warnings and Precautions (5.1)]. 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 (6.2)].
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.
5.4 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.
5.5 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
5.6 Cardiac Arrhythmias
Cardiac arrhythmias have been observed in patients receiving MultiHance
in clinical trials [see Adverse Reactions (6.1)]. Assess patients
for underlying conditions or medications that predispose to arrhythmias.
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 systematically
5.7 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.
6 Adverse Reactions
The following adverse reactions are discussed in greater detail in
other sections of the label:
- Nephrogenic systemic fibrosis [see Warnings and
- Hypersensitivity reactions [see Warnings and Precautions (5.2)]
6.1 Clinical Trials
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 practice.
In all clinical trials with MultiHance, a total of 4967
adult subjects (137 healthy volunteers and 4830 patients) received
MultiHance at doses ranging from 0.005 to 0.4 mmol/kg. There were
2838 (57%) men and 2129 (43%) women with a mean age of 56.5 years
(range 18 to 93 years). A total of 4403 (89%) subjects were Caucasian,
134 (3%) Black, 275 (6%) Asian, 40 (1%) Hispanic, 70 (1%) in other
racial groups, and for 45 (1%) subjects, race was not reported.
The most commonly reported adverse reactions
in adult subjects who received MultiHance were nausea (1.3%) and headache
(1.2%). Most adverse reactions were mild to moderate in intensity.
One subject experienced a serious anaphylactoid reaction with laryngeal
spasm and dyspnea [see Warnings and Precautions (5.2)]. Serious adverse reactions
consisting of convulsions, pulmonary edema, acute necrotizing pancreatitis,
and anaphylactoid reactions were reported in 0.1% of subjects in clinical
Adverse reactions that
occurred in at least 0.5% of 4967 adult subjects who received MultiHance
are listed below (Table 2), in decreasing order of occurrence within
TABLE 2: ADVERSE REACTIONS REPORTED IN ≥ 0.5% OF ADULT SUBJECTS
WHO RECEIVED MULTIHANCE IN CLINICAL TRIALS
|Number of subjects
|Number of subjects
with any adverse reaction||517(10.4%)|
| 67 (1.3%)|
and Administration Site Disorders|
Injection Site Reaction
| 54 (1.1%)|
| 60 (1.2%)|
The following adverse reactions occurred
in less than 0.5% of the 4967 adult subjects who received MultiHance.
Serious adverse reactions described above are not repeated below.
Blood and Lymphatic System Disorders: Basophilia;
Cardiac Disorders: Atrioventricular block first degree;
Eye Disorders: Eye pruritus, eye swelling, ocular
hyperemia, visual disturbance;
Disorders: Abdominal pain or discomfort, diarrhea,
dry mouth, lip swelling, paraesthesia oral, tongue edema, vomiting;
General Disorders and Administration Site Conditions: Chest pain or discomfort, chills, malaise;
Immune System Disorders: Hypersensitivity;
Investigations: Nonspecific changes
in laboratory tests (including hematology, blood chemistry, liver
enzymes and urinalysis), blood pressure and electrocardiogram parameters
(including PR, QRS and QT intervals and ST-T segment changes).
Musculoskeletal and Connective Tissue Disorders: Myalgia;
Nervous System Disorders: Parosmia, tremor;
Thoracic and Mediastinal Disorders: Dyspnea, laryngospasm,
nasal congestion, sneezing, wheezing;
and Subcutaneous Tissue Disorders: Hyperhidrosis,
pruritus, rash, swelling face, urticaria.
In clinical trials of MultiHance in MRI
of the CNS, 307 pediatric subjects received MultiHance at a dose of
0.1 mmol/kg. A total of 160 (52%) subjects were male and the overall
mean age was 6.0 years (range, 2 days to 17 years). A total of 211
(69%) subjects were Caucasian, 24 (8%) Black, 15 (5%) Asian, 39 (13%),
Hispanic, 2 (<1%) in other racial groups, and for 16 (5%), race
was not reported.
were reported for 14 (4.6%) of the subjects. The frequency and the
nature of the adverse reactions were similar to those seen in the
adult patients. The most commonly reported adverse reactions were
vomiting (1.0%), pyrexia (0.7%), and hyperhidrosis (0.7%). No subject
died during study participation.
6.2 Post-Marketing Experience
The following adverse reactions have been
identified during post approval use of MultiHance. Because these
reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Immune System Disorders: Anaphylactic,
anaphylactoid and hypersensitivity reactions manifested with various
degrees of severity up to anaphylactic shock, loss of consciousness
and death. The reactions generally involved signs or symptoms of
respiratory, cardiovascular, and/or mucocutaneous abnormalities.
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 [see Warnings and Precautions (5.4)].
Adverse events with variable
onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and
heterogeneous clusters of symptoms in the neurological, cutaneous,
and musculoskeletal systems.
Skin: Gadolinium associated
7.1 Transporter-Based Drug-Drug Interactions
MultiHance and other drugs may compete for the canalicular multispecific organic anion transporter (MOAT also referred to as MRP2 or ABCC2). Therefore MultiHance may prolong the systemic exposure of drugs such as cisplatin, antracyclines (e.g. doxorubicin, daunorubicin), vinca alkaloids (e.g. vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel. In particular, consider the potential for prolonged drug exposure in patients with decreased MOAT activity (e.g. Dubin Johnson syndrome).
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 during pregnancy 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.
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.
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 intravenously
administered 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.
8.4 Pediatric Use
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 (14)]. Adverse reactions in pediatric patients were
similar to those reported in adults [see Adverse Reactions
(6.1)]. 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 [see Dosage and Administration
(2.1), Pharmacokinetics (12.3)]. The safety of MultiHance
has not been established in preterm neonates.
8.5 Geriatric Use
Of the total number of 4967 adult subjects in clinical studies of MultiHance, 33% were 65 and over. 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.
Clinical consequences of overdosage with MultiHance have not been reported. Treatment of an overdosage should be directed toward support of vital functions and prompt institution of symptomatic therapy. In a Phase 1 clinical study, doses up to 0.4 mmol/kg were administered to patients. MultiHance has been shown to be dialyzable [see Clinical Pharmacology (12.3)].
MultiHance injection is supplied as a sterile, nonpyrogenic, clear, colorless to slightly yellow, aqueous solution intended for intravenous use only. Each mL of MultiHance contains 529 mg gadobenate dimeglumine and water for injection. MultiHance contains no preservatives.
Gadobenate dimeglumine is chemically designated as (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)- 1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)] gadolinate(2-) dihydrogen compound with 1-deoxy-1-(methylamino)-D-glucitol (1:2) with a molecular weight of 1058.2 and an empirical formula of C22H28GdN3O11 • 2C7H17NO5. The structural formula is as follows:
MultiHance has a pH of 6.5-7.5. Pertinent physicochemical parameters are provided below:
|Osmolality||1.970 osmol/kg @ 37°C|
|Viscosity||5.3 mPas @ 37°C|
|Density||1.220 g/mL @ 20°C|
MultiHance has an osmolality 6.9 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use.
12.1 Mechanism Of Action
Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The large magnetic moment produced by the paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue.
In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.
Unlike other tested paramagnetic contrast agents (See Table 3), MultiHance
demonstrates weak and transient interactions with serum proteins that
causes slowing in the molecular tumbling dynamics, resulting in strong
increases in relaxivity in solutions containing serum proteins. The
improved relaxation effect can contribute to increased contrast-to-noise
ratio and lesion-to-brain ratio, which may improve visualization.
TABLE 3: RELAXIVITY (mM-1s-1) OF GADOLINIUM CHELATES
r2 relaxivities indicate the efficiency in
shortening T1 and T2 relaxation times, respectively.|
1 In heparinized human plasma, at 39°C.
2 In citrated human plasma, at 37°C.
Disruption of the blood-brain barrier
or abnormal vascularity allows enhancement by MultiHance of lesions
such as neoplasms, abscesses, and infarcts. Uptake of MultiHance
into hepatocytes has been demonstrated.
Three single-dose intravenous studies were conducted in 32 healthy
male subjects to assess the pharmacokinetics of gadobenate dimeglumine.
The doses administered in these studies ranged from 0.005 to 0.4
mmol/kg. Upon injection, the meglumine salt is completely dissociated
from the gadobenate dimeglumine complex. Thus, the pharmacokinetics
is based on the assay of gadobenate ion, the MRI contrast effective
ion in gadobenate dimeglumine. Data for plasma concentration and
area under the curve demonstrated linear dependence on the administered
dose. The pharmacokinetics of gadobenate ion following intravenous
administration can be best described using a two-compartment model.
Gadobenate ion has a rapid distribution half-life (reported
as mean ± SD) of 0.084 ± 0.012 to 0.605 ± 0.072 hours. Volume of
distribution of the central compartment ranged from 0.074 ± 0.017
to 0.158 ± 0.038 L/kg, and estimates of volume of distribution by
area ranged from 0.170 ± 0.016 to 0.282 ± 0.079 L/kg. These latter
estimates are approximately equivalent to the average volume of extracellular
body water in man. In vitro studies showed no appreciable binding
of gadobenate ion to human serum proteins.
Following GBCA administration, gadolinium
is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].
Gadobenate ion is eliminated predominately via
the kidneys, with 78% to 96% of an administered dose recovered in
the urine. Total plasma clearance and renal clearance estimates of
gadobenate ion were similar, ranging from 0.093 ± 0.010 to 0.133 ±
0.270 L/hr/kg and 0.082 ± 0.007 to 0.104 ± 0.039 L/hr/kg, respectively.
The clearance is similar to that of substances that are subject to
glomerular filtration. The mean elimination half-life ranged from
1.17 ± 0.26 to 2.02 ± 0.60 hours. A small percentage of the administered
dose (0.6% to 4%) is eliminated via the biliary route and recovered
There was no detectable biotransformation of gadobenate
ion. Dissociation of gadobenate ion in vivo has been shown to be minimal,
with less than 1% of the free chelating agent being recovered alone
in Special Populations
Renal Impairment: A single intravenous dose of 0.2 mmol/kg of MultiHance
was administered to 20 subjects with impaired renal function (6 men
and 3 women with moderate renal impairment [urine creatinine clearance
>30 to <60 mL/min] and 5 men and 6 women with severe renal impairment
[urine creatinine clearance >10 to <30 mL/min]). Mean estimates
of the elimination half-life were 6.1 ± 3.0 and 9.5 ± 3.1 hours for
the moderate and severe renal impairment groups, respectively as compared
with 1.0 to 2.0 hours in healthy volunteers.
Hemodialysis: A single intravenous dose of 0.2 mmol/kg of MultiHance was
administered to 11 subjects (5 males and 6 females) with end-stage
renal disease requiring hemodialysis to determine the pharmacokinetics
and dialyzability of gadobenate. Approximately 72% of the dose was
recovered by hemodialysis over a 4-hour period. The mean elimination
half-life on dialysis was 1.21 ± 0.29 hours as compared with 42.4
± 24.4 hours when off dialysis.
Hepatic Impairment: A single intravenous dose of 0.1 mmol/kg of MultiHance was administered
to 11 subjects (8 males and 3 females) with impaired liver function
(Class B or C modified Child-Pugh Classification). Hepatic impairment
had little effect on the pharmacokinetics of MultiHance with the parameters
being similar to those calculated for healthy subjects.
Gender, Age, Race: A multiple regression analysis performed using pooled
data from several pharmacokinetic studies found no significant effect
of sex upon the pharmacokinetics of gadobenate. Clearance appeared
to decrease slightly with increasing age. Since variations due to
age appeared marginal, dosage adjustment for geriatric population
is not recommended. Pharmacokinetic differences due to race have not
been systematically studied.
Pediatric: A population
pharmacokinetic analysis incorporated data from 25 healthy subjects
(14 males and 11 females) and 15 subjects undergoing MR imaging of
the central nervous system (7 males and 8 females) between ages of
2 and 16 years. The subjects received a single intravenous dose of
0.1 mmol/kg of MultiHance. The geometric mean Cmax was 62.3 μg/mL (n=16) in children 2 to 5 years of age, and 64.2
μg/mL (n=24) in children older than 5 years. The geometric mean AUC 0-∞ was 77.9 μg-h/mL in children 2-5 years of age (n=16)
and 82.6 μg-h/mL in children older than 5 years (n=24). The geometric
mean half-life was 1.2 hours in children 2 to 5 years of age and 0.93
hours in children older than 5 years. There was no significant gender-related
difference in the pharmacokinetic parameters in the pediatric patients.
Over 80% of the dose was recovered in urine after 24 hours.
indicate similar AUC and Cmax values for MultiHance in pediatric subjects
less than 2 years when compared to those reported for adults; no age-based
dose adjustment is necessary for this pediatric population.
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of MultiHance.
The results for MultiHance were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) 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).
14.1 Mri Of The Cns
MultiHance was evaluated in 426 adult patients
in 2 controlled clinical trials of the central nervous system (Study
A and Study B), enrolling 217 men and 209 women with a mean age of
52 years (range 18 to 88 years). The racial and ethnic representations
were 88% Caucasian, 6% Black, 4% Hispanic, 1% Asian, and 1% other
racial or ethnic groups. These trials were designed to compare MultiHance
contrast MRI to non-contrast MRI alone. In Study A, patients highly
suspected of having a lesion(s) of the CNS based on nuclear medicine
imaging, computed tomography (CT), contrast CT, MRI, contrast- MRI,
or angiography were randomized to receive two MRI evaluations with
0.05 mmol/kg (n=140) or 0.1 mmol/kg (n=136) of MultiHance. In Study
B, patients with known metastatic disease to the CNS were randomized
to receive two MRI evaluations with 0.05 mmol/kg (n=74) or 0.1 mmol/kg
(n=76) of MultiHance. MRI scans were performed pre-contrast and within
5 minutes after each injection. The studies were designed to evaluate
the effect of MultiHance MRI compared to the non-contrast MRI on a
lesion level. Pre-contrast, post-contrast, and pre-plus-post contrast
images (paired images) were independently evaluated by three blinded
readers. The images were evaluated for the following endpoints using
a scale from 0 to 4: the degree of lesion border delineation, the
degree of visualization of lesion internal morphology, and the degree
of lesion contrast enhancement. Lesion counting was also performed
for the pre-contrast and paired image sets.
The 0.1 mmol/kg dose of MultiHance demonstrated consistently
better visualization for all readers for all visualization endpoints.
However, the 0.05 mmol/kg dose of MultiHance provided inconsistent
visualization results between readers.
Comparison of pre-contrast versus post-contrast (0.1
mmol/kg) images showed that the mean score differences were significant
and favored contrast for subjects in Study B (all subjects with known
metastatic lesions) and for subjects with known tumors in Study A.
However, the mean score differences between the pre-contrast and
post-contrast images were not significant for non-tumor patients in
Study A. These negative results may be attributed to a lack of lesion
enhancement in non-tumor CNS disease.
Table 4 shows a comparison of paired images (pre-and
post-contrast) versus pre-contrast images with respect to the difference
in the mean score and with respect to the proportion of lesions read
as better, worse, or the same as the pre-contrast MRI images. Table
4 shows that based on a lesion-level analysis 0.1 mmol/kg MultiHance
provided a statistically significant improvement for the three structural
parameters evaluated. Also, more lesions were seen in the paired
images than in the pre-contrast images alone.
Table 4: LESION LEVEL RESULTS OF MRI CENTRAL NERVOUS SYSTEM
ADULT STUDIES WITH 0.1 mmol/kg MULTIHANCE
Difference of means = (paired mean) - (pre mean)|
= paired score is less than the pre score
Same = paired
score is the same as the pre score
Better = paired score
is greater than the pre score
* Statistically significant for the mean (paired t test)
| ||Reader 1||Reader 2||Reader 3||Reader 1||Reader 2||Reader 3|
|Endpoints||N = 395||N = 384||N = 299||N = 245||N = 275||N = 254|
|Border Delineation: || || || || || || |
|Difference of Means (a)||0.8*||0.6*||0.8*||1.8*||1.5*||1.9*|
|Internal Morphology:|| || || || || || |
|Difference of Means||0.8*||0.6*||0.7*||1.7*||1.4*||2.1*|
|Contrast Enhancement:|| || || || || || |
|Difference of Means||0.7*||0.5*||0.8*||1.9*||1.3*||1.9*|
Pediatric 2 to 17 years
The efficacy and safety of MultiHance were evaluated in 92 pediatric
patients with known or highly suspected disease of the central nervous
system. MRI scans were performed pre-contrast and within 3 to 10
minutes following the administration of MultiHance 0.1 mmol/kg. Pre-contrast,
post-contrast, and pre-plus-post contrast images (paired images) were
independently evaluated by three blinded readers on a lesion level.
The images were evaluated for the same endpoints as in the adult
central nervous system trials using a scale from 0 to 4: the degree
of lesion border delineation, the degree of visualization of lesion
internal morphology, and the degree of lesion contrast enhancement.
Lesion counting was also performed for the pre-contrast and paired
image sets. The pre-contrast versus the paired image set was the
primary comparison. Forty-nine percent of study subjects were male
and the overall mean age was 10.6 years (range 2 to 17 years). The
racial and ethnic representations were 77% Caucasian, 13% Asian, 5%
Black, and 4% other racial or ethnic groups. MultiHance increased
lesion border delineation, lesion internal morphology, and lesion
contrast enhancement relative to non-contrast and these results were
comparable to those seen in adults.
Pediatrics below 2 years
of 90 pediatric patients younger than 2 years of age was performed
which supports extrapolation of CNS efficacy findings from adults
and older pediatric patients. Three independent, blinded readers evaluated
pre-contrast MRI image sets and paired pre-plus-post-contrast MRI
image sets using MultiHance and rated the images according to three
co-primary endpoints at a lesion level for the primary analysis. Two
of the three readers reported improvement in the paired image sets
in each of the three co-primary endpoints of lesion border delineation,
visualization of lesion internal morphology, and lesion contrast enhancement.
14.2 Mra Of Renal And Aorto-Ilio-Femoral Vessels
Safety and efficacy of MultiHance for use
in MRA were evaluated in two prospective, multi-center, open-label,
clinical trials (one for each arterial vascular territory: renal and
aorto-ilio-femoral). Out of 580 patients who received MultiHance
in these two trials, 62.2% were men and 90.9% were Caucasian; the
average age was 63.4 years (range 18 to 93 years). In both trials,
patients with known or suspected arterial disease underwent MRA with
and without MultiHance as well as catheter-based digital subtraction
angiography (DSA). Assessment of diagnostic efficacy for detecting/excluding
clinically significant steno-occlusive disease (≥ 51% stenosis measured
with electronic calipers) was based on comparisons of sensitivity
and specificity between MultiHance MRA and non-contrast MRA, with
DSA as a reference standard.
In each vascular territory, the primary efficacy analyses were designed
to demonstrate superiority in sensitivity and non-inferiority in specificity
of MultiHance MRA to non-contrast MRA at the vessel-segment level.
The interpretation of MRA images from both trials was conducted by
three independent radiologist readers who were blinded to clinical
data, including the DSA results. The pre-specified success criteria
were to be achieved by at least the same two readers for all primary
Results of both trials
showed a statistically significant increase in sensitivity and specificity
of MultiHance MRA over non-contrast MRA in detecting clinically significant
steno-occlusive disease. Table 5 summarizes the efficacy results by
|TABLE 5. PERFORMANCE CHARACTERISTICS
OF MULTIHANCE-MRA AND NON-CONTRAST MRA|
on General Delta Method)|
|[A] – [B]|
|[A] – [B]|
|2||65.2% ||52.5% ||12.6 |
|94.2% ||89.4% ||4.9|
|3||69.0% ||59.1% ||10.0 |
|90.0% ||75.3% ||14.9|
| ||RENAL ARTERIES|
|[A] – [B]|
|[A] – [B]|
16.1 How Supplied
MultiHance (gadobenate dimeglumine) is
a clear, colorless to slightly yellow solution containing 529 mg gadobenate
dimeglumine per mL. MultiHance is supplied in glass vials; each single
dose vial is rubber stoppered with an aluminum seal and the contents
are sterile. MultiHance is supplied in boxes of:
Five 5 mL single dose 10 mL vials (NDC
Five 10 mL single dose 20 mL vials (NDC
Five 15 mL single dose 20 mL vials (NDC
Five 20 mL single dose 20 mL vials (NDC
16.2 Storage And Handling
at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature].
Do not freeze.
17 Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling
Instruct patients to inform their physician
- 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
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
Inform patients that they may
- 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 (5.3)].
S Patent No. 4,916,246
Inc. - Monroe Twp, NJ 08831
By BIPSO GmbH. - 78224 Singen
Revised April 2018
Package Label.Principal Display Panel
MultiHance® Injection 15 mL
* Please review the disclaimer below.