Document
DailyMed Label: MultiHance
Title
DailyMed Label: MultiHance
Date
2024
Document type
DailyMed Prescription
Name
MultiHance
Generic name
gadobenate dimeglumine
Manufacturer
BRACCO DIAGNOSTICS INC
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Product information
NDC: 0270-5164
Description
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 C 22 H 28 GdN 3 O 11 • 2C 7 H 17 NO 5 . 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.
MultiHance Structure
Indications
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. (1.1)
magnetic resonance angiography (MRA) to evaluate adults
with known or suspected renal or aorto-ilio-femoral occlusive vascular
disease. (1.2)
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.
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.
Dosage
The recommended dose of MultiHance is 0.2 mL/kg (0.1 mmol/kg)
administered as a rapid bolus intravenous injection.
For MRI of the CNS in pediatric patients below 2 years of
age the recommended dosage range is 0.1 to 0.2 mL/kg.
To ensure complete injection of the contrast medium, follow
the injection with a saline flush of at least 5 mL in MRI of the CNS
and at least 20 mL in MRA. ( 2 )
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
of MultiHance.
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.
*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: CNS IMAGING
(ADULTS AND PEDIATRICS ≥2 YEARS OF AGE*) AND MRA IMAGING (ADULTS ONLY)
0.1mM/kg dose
Kilograms (Kg)
Pounds (lb)
Volume, Milliliters
(mL)
2.5
5.5
0.5
5
11
1.0
10
22
2.0
15
33
3.0
20
44
4.0
25
55
5.0
30
66
6.0
35
77
7.0
40
88
8.0
45
99
9.0
50
110
10.0
55
121
11.0
60
132
12.0
65
143
13.0
70
154
14.0
75
165
15.0
80
176
16.0
85
187
17.0
90
198
18.0
95
209
19.0
100
220
20.0
105
231
21.0
110
242
22.0
115
253
23.0
120
264
24.0
125
275
25.0
130
286
26.0
135
297
27.0
140
308
28.0
145
319
29.0
150
330
30.0
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.
Dosage forms
MultiHance is a sterile, nonpyrogenic, clear,
colorless to slightly yellow aqueous solution for intravenous use
only, containing 529 mg gadobenate dimeglumine per mL.
Each mL of MultiHance Injection contains
529 mg gadobenate dimeglumine and is available in single use vials. (3)
Contraindications
MultiHance is contraindicated in patients with known allergic or
hypersensitivity reactions to gadolinium-based contrast agents [
see Warnings and Precautions (5.3)
].
MultiHance is contraindicated in patients
with known allergic or hypersensitivity reactions to gadolinium-based
contrast agents. (4)
Warnings
Hypersensitivity: anaphylactic/anaphylactoid reactions with
cardiovascular, respiratory and cutaneous manifestations, ranging
from mild to severe reactions including shock can occur. Monitor patients
closely for need of emergency cardiorespiratory support. (5.3)
Gadolinium is retained for months or years in brain, bone,
and other organs. (5.4)
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) ] .
GBCAs increase the risk for nephrogenic systemic fibrosis
(NSF) among patients with impaired elimination of the drugs. Avoid
use of MultiHance 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/1.73m 2 ) as well as patients with acute kidney injury. The
risk appears lower for patients with chronic, moderate kidney disease
(GFR 30-59 mL/min/1.73m 2 ) and little, if
any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m 2 ). 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)
].
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. 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 (5.2) ] . 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) ] .
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.
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 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 (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
studied.
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.
Adverse reactions
The following adverse reactions are discussed in greater detail in
other sections of the label:
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, anthracyclines (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).
Use in_specific_populations
Pregnancy: Use only if imaging
is essential during pregnancy and cannot be delayed. ( 8.1 )
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 (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%, 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. 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.
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.
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 ( 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.
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.
How supplied
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 0270-5164-12) Five 10 mL single
dose 20 mL vials (NDC 0270-5164-13) Five 15 mL
single dose 20 mL vials (NDC 0270-5164-14) Five
20 mL single dose 20 mL vials (NDC 0270-5164-15)
16.2 Storage and Handling
Store at 25°C (77°F), excursions permitted to 15-30°C
(59-86°F) [see USP Controlled Room Temperature]. Do not freeze.
Clinical pharmacology
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 –1 s –1 ) OF GADOLINIUM CHELATES
r 1 and
r 2 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. --
Not available
Human
plasma
r 1
r 2
Gadobenate
9.7 1
12.5 1
Gadopentetate
4.9 1
6.3 1
Gadodiamide
5.4 2
--
Gadoteridol
5.4 2
--
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.
Distribution
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 (5.4) ] .
Elimination
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
in feces.
Metabolism
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 feces.
Pharmacokinetics 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 C max 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. Pharmacokinetic simulations indicate similar
AUC and C max 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.
Nonclinical toxicology
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).
Clinical studies
Adults: 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.
(a)
Difference of means = (paired mean) - (pre mean) (b) Worse
= 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)
Table 4: LESION LEVEL RESULTS OF MRI CENTRAL NERVOUS SYSTEM ADULT
STUDIES WITH 0.1 mmol/kg MULTIHANCE
Study
A
Study
B
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*
Worse (b) Same Better
44 (11%) 146 (37%) 205 (52%)
61 (16%) 168 (44%) 155 (40%)
57 (19%) 89 (30%) 153 (51%)
13 (5%) 11 (5%) 221 (90%)
24 (9%) 19 (7%) 232 (84%)
15 (6%) 18 (7%) 221 (87%)
Internal Morphology:
Difference of Means
0.8*
0.6*
0.7*
1.7*
1.4*
2.1*
Worse Same Better
37 (10%) 147 (37%) 211 (53%)
63 (17%) 151 (39%) 170 (44%)
62 (21%) 84 (28%) 153 (51%)
13 (5%) 16 (7%) 216 (88%)
26 (10%) 22 (8%) 227 (82%)
14 (5%) 22 (9%) 218 (86%)
Contrast Enhancement:
Difference of Means
0.7*
0.5*
0.8*
1.9*
1.3*
1.9*
Worse Same Better
75 (19%) 148 (37%) 172 (44%)
74 (19%) 152 (40%) 158 (41%)
50 (17%) 109 (36%) 140 (47%)
13 (5%) 11 (5%) 221 (90%)
32 (12%) 21 (7%) 222 (81%)
17 (7%) 14 (5%) 223 (88%)
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 A study
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.
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 analyses.
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 reader.
TABLE 5. PERFORMANCE CHARACTERISTICS
OF MULTIHANCE-MRA AND NON-CONTRAST MRA
* (Based
on General Delta Method)
READER
AORTO-ILIO-FEMORAL
ARTERIES
SENSITIVITY
SPECIFICITY
MultiHance MRA [A]
Non-contrast MRA
[B]
[A] – [B] (95% CI)*
MultiHance MRA [A]
Non-contrast MRA
[B]
[A] – [B] (95% CI)*
1
77.8%
73.7%
4.5 (1.5, 7.6)
88.1%
78.5%
10.0 (7.3, 12.6)
2
65.2%
52.5%
12.6 (8.5, 16.6)
94.2%
89.4%
4.9 (2.7, 7.1)
3
69.0%
59.1%
10.0 (6.1, 14.0)
90.0%
75.3%
14.9 (12.1, 17.8)
READER
RENAL ARTERIES
SENSITIVITY
SPECIFICITY
MultiHance MRA [A]
Non-contrast MRA
[B]
[A] – [B] (95% CI)*
MultiHance MRA [A]
Non-contrast MRA
[B]
[A] – [B] (95% CI)*
1
67.8%
47.0%
20.8 (12.8, 28.9)
94.0%
86.1%
8.3 (4.2, 12.4)
2
62.4%
46.7%
16.2 (6.8, 25.6)
94.0%
83.5%
10.3 (5.5, 15.0)
3
65.5%
39.6%
25.3 (15.9, 34.6)
94.7%
87.3%
8.0 (3.6, 12.5)
Package label
MultiHance ® Injection 15 mL NDC 0270–5164–14
multihance-carton
multihance-15-ml-vial-label
1 organization
1 product
Product
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Bracco Diagnostics Inc