Multihance Prescribing Information
(GBCAs) can cause serious adverse reactions including death, coma,
encephalopathy, and seizures. MultiHance is not approved for intrathecal
use
with Intrathecal Use
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
systemic fibrosis (NSF) among patients with impaired elimination of
the drugs. Avoid use of MultiHance 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.
highest among patients with:
- chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or
- acute kidney injury.
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 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.
Fibrosis
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/1.73m2) 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
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
and Administration (2)and Clinical
Pharmacology (12)]
- 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 tissues1.1 Magnetic Resonance
Imaging (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. - magnetic resonance angiography (MRA) to evaluate adults
with known or suspected renal or aorto-ilio-femoral occlusive vascular
disease.1.2 Magnetic Resonance
Angiography (MRA) of Renal and Aorto-ilio-femoral VesselsMultiHance is indicated for use in magnetic
resonance angiography (MRA) to evaluate adults with known or suspected
renal or aorto-ilio-femoral occlusive vascular disease.
INFUSION
- 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 DOSAGE AND ADMINISTRATIONPHARMACY BULK PACKAGE – NOT FOR DIRECT
INFUSION- 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)
2.1 Dosing and Imaging
Instructions2.1.1 MRI of the
CNSIn 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.2.1.2 MRA of Renal
and Aorto-ilio-femoral VesselsFor 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:
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 2.3 AdministrationInspect 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.2.4 Directions for Proper
Use of MultiHance MultipackThe pharmacy bulk package is used as a multiple dose container with
an appropriate transfer device to fill empty syringes.MultiHance Multipack injection should be
drawn into the syringe and administered using sterile technique. Unused
portions of the drug must be discarded.When MultiHance Multipack injection is to be injected
using plastic disposable syringes, the agent should be drawn into
the syringe and used immediately.- The transferring of MultiHance (gadobenate dimeglumine)
injection from the Pharmacy Bulk Package should be performed in a
suitable work area, such as a laminar flow hood, utilizing aseptic
technique. - The container closure may be penetrated only one time, utilizing
a suitable transfer device. Once the pharmacy bulk package is punctured,
it should not be removed from the aseptic work area during the entire
period of use. - The withdrawal of container contents should be accomplished
without delay. However, should this not be possible, a maximum time
of 8 hours from initial closure entry is permitted to complete fluid
transfer operation. Any unused MultiHance Multipack injection must
be discarded 8 hours after initial puncture of the bulk package. - Temperature of container after the closure has been entered
should not exceed 25°C (77°F).
- The recommended dose of MultiHance is 0.2 mL/kg (0.1 mmol/kg)
MultiHance is a sterile, nonpyrogenic, clear,
colorless to slightly yellow aqueous solution for intravenous use
only, containing 529 mg gadobenate dimeglumine per mL.
Pregnancy: Use only if imaging
is essential during pregnancy and cannot be delayed. (
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
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
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.
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.
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.
MultiHance is contraindicated in patients with known allergic or
hypersensitivity reactions to gadolinium-based contrast agents
Reactions
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.