Prohance Prescribing Information
contrast agents (GBCAs) can cause serious adverse reactions including
death, coma, encephalopathy, and seizures. ProHance is not approved
for intrathecal use
Intrathecal Use
Intrathecal administration of GBCAs can cause serious adverse reactions
including death, coma, encephalopathy, and seizures. The safety and
effectiveness of ProHance have not been established with intrathecal
use. ProHance is not approved for intrathecal use
and Administration ]
systemic fibrosis (NSF) among patients with impaired elimination of
the drugs. Avoid use of ProHance 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 less than 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 greater than 60 years, hypertension or diabetes), estimate the
glomerular filtration rate (GFR) through laboratory testing.
at highest risk for NSF, do not exceed the recommended ProHance dose
and allow a sufficient period of time for elimination of the drug
from the body prior to re-administration
Precautions (
Fibrosis
GBCAs
increase the risk for nephrogenic systemic fibrosis (NSF) among patients
with impaired elimination of the drugs. Avoid use of ProHance among
these patients unless the diagnostic information is essential and
not available with non-contrast MRI or other modalities. The GBCA-associated
NSF risk appears highest for patients with chronic, severe kidney
disease (GFR less than 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 ProHance Multipack 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 (for example,
age greater than 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 ProHance 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 Page 4 elimination.
The usefulness of hemodialysis in the prevention of NSF is unknown
ProHance Multipack is a gadolinium-based
contrast agent indicated for magnetic resonance imaging (MRI) to visualize:
- lesions with disrupted blood brain barrier and/or abnormal
vascularity in the brain (intracranial lesions), spine and associated
tissues in adults and pediatric patients, including term neonates
()1.1 MRI of the Central
Nervous System (CNS)ProHance is indicated for magnetic resonance
imaging (MRI) in adults and pediatric patients including term neonates
to visualize lesions with disrupted blood brain barrier and/or abnormal
vascularity in the brain (intracranial lesions), spine and associated
tissues. - lesions in the head and neck in adults ()
1.2 MRI of Extracranial/Extraspinal
TissuesProHance
is indicated for MRI in adults to visualize lesions in the head and
neck.
- Dispense multiple single doses into separate sterile syringes
for intravenous administration ()2.3 Directions for Proper
Use of Pharmacy Bulk PackageNOT FOR DIRECT INFUSION
The pharmacy bulk package is used as a multiple dose container with an appropriate transfer device to fill empty sterile syringes. Use the following procedures when transferring ProHance from the pharmacy bulk package to individual syringes:- Use of this product is restricted to a suitable work area, such as a laminar flow hood, utilizing aseptic technique
- Prior to entering the vial, remove the seal and cleanse the rubber closure with a suitable antiseptic agent
- The container closure may be penetrated only one time, utilizing a suitable transfer device or dispensing set that allows measured dispensing of the contents
- Once the pharmacy bulk package is punctured, it should not be removed from the aseptic work area during the entire period of use
- Withdrawal of container contents should be accomplished without delay. A maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operations
- Any unused contents must be discarded by 8 hours after initial puncture of the bulk package
- Once drawn into syringe, administer transferred agent promptly for single-dose administration
- Recommended dose in adult and pediatric patients is 0.2
mL/kg (0.1 mmol/kg) body weight administered as rapid intravenous
infusion or bolus ()2.1 Recommended DoseThe recommended dose for adult and pediatric
patients, including term neonates, is 0.2 mL/kg (0.1 mmol/kg) administered
as a rapid intravenous infusion (10 mL/min to 60 mL/min) or bolus
(greater than 60 mL/min). Table 1 provides weight-adjusted recommended
dose volumes.Table 1: Recommended
Volume of ProHance Injection by Body WeightBody Weight (kg)Volume to be Administered
(mL)2.5 0.5 5 1 10 2 20 4 30 6 40 8 50 10 60 12 70 14 80 16 90 18 100 20 110 22 120 24 130 26 140 28 150 30 MRI of the:
CNS in Adults- A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be given
up to 30 minutes after the first dose in adult patients with normal
renal function suspected of having poorly visualized CNS lesions,
in the presence of negative or equivocal scans - The safety and efficacy of supplementary dosing have not
been established in pediatric patients
- A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be given
- Follow injection with a saline flush of at least 5 mL normal
saline ()2.1 Recommended DoseThe recommended dose for adult and pediatric
patients, including term neonates, is 0.2 mL/kg (0.1 mmol/kg) administered
as a rapid intravenous infusion (10 mL/min to 60 mL/min) or bolus
(greater than 60 mL/min). Table 1 provides weight-adjusted recommended
dose volumes.Table 1: Recommended
Volume of ProHance Injection by Body WeightBody Weight (kg)Volume to be Administered
(mL)2.5 0.5 5 1 10 2 20 4 30 6 40 8 50 10 60 12 70 14 80 16 90 18 100 20 110 22 120 24 130 26 140 28 150 30 MRI of the:
CNS in Adults- A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be given
up to 30 minutes after the first dose in adult patients with normal
renal function suspected of having poorly visualized CNS lesions,
in the presence of negative or equivocal scans - The safety and efficacy of supplementary dosing have not
been established in pediatric patients
- A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be given
ProHance Multipack is supplied as a sterile, nonpyrogenic, and colorless to slightly yellow solution available in 50 mL and 100 mL pharmacy bulk packages for intravenous administration. Each mL contains 279.3 mg (0.5 mmol/mL) of gadoteridol for injection.
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
risks of gadolinium to the fetus, use ProHance only if imaging is
essential during pregnancy and cannot be delayed.
In animal reproduction studies in rats,
gadoteridol doubled the incidence of post-implantation loss at up
to 16 times the recommended human dose (RHD). There were no adverse
developmental effects observed in rabbits with intravenous administration
of gadoteridol during organogenesis at doses up to 19 times the recommended
human dose of 0.1 mmol/kg
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 agent is visualized
in the placenta and fetal tissues after maternal GBCA administration.
Cohort studies and case reports on exposure to GBCAs during pregnancy
have not reported a clear association between GBCAs and adverse effects
in the exposed neonates. However, a retrospective cohort study, comparing
pregnant women who had a GBCA MRI to pregnant women who did not have
an MRI, reported a higher occurrence of stillbirths and neonatal deaths
in the group receiving GBCA MRI. Limitations of this study include
a lack of comparison with non-contrast MRI and lack of information
about the maternal indication for MRI.
Gadolinium
Retention
GBCAs administered to pregnant non-human primates
(0.1 mmol/kg on gestational days 85 and 135) result in measurable
gadolinium concentration in the offspring in bone, brain, skin, liver,
kidney, and spleen for at least 7 months. GBCAs administered to pregnant
mice (2 mmol/kg daily on gestational days 16 through 19) result in
measurable gadolinium concentrations in the pups in bone, brain, kidney,
liver, blood, muscle, and spleen at one-month postnatal age.
Reproductive Toxicology
Gadoteridol was administered in intravenous doses of 0, 0.375, 1.5,
6.0, and 10 mmol/kg/day [0.6, 2.4, 9.7, and 16 times the recommended
human dose (RHD) based on body surface area (BSA)] to female rats
from gestational day (GD)6 until GD17. Gadoteridol at 10 mmol/kg/day
for 12 days during gestation doubled the incidence of post-implantation
loss. When rats were administered 6.0 or 10.0 mmol/kg/day for 12 days,
an increase in spontaneous locomotor activity was observed in the
offspring. Pregnant rabbits were administered gadoteridol in intravenous
doses of 0, 0.4, 1.5, and 6 mmol/kg/day (1.3, 4.8, and 19.4 times
the RHD based on BSA) from GD6 to GD18. Gadoteridol increased the
incidence of spontaneous abortion and early delivery in rabbits administered
6 mmol/kg/day for 13 days during gestation.
ProHance
is contraindicated in patients with known allergic or hypersensitivity
reactions to ProHance
Anaphylactic and anaphylactoid reactions have
been reported, involving cardiovascular, respiratory, and/or cutaneous
manifestations. Some patients experienced circulatory collapse and
died. In most cases, initial symptoms occurred within minutes of ProHance
administration and resolved with prompt emergency treatment.
Prior to ProHance administration,
ensure the availability of trained personnel and medications to treat
hypersensitivity reactions. Consider the risk for hypersensitivity
reactions, especially in patients with a history of hypersensitivity
reactions or a history of asthma or other allergic disorders. If such
a reaction occurs, stop ProHance and immediately begin appropriate
therapy. Observe patients for signs and symptoms of a hypersensitivity
reaction during and for up to 2 hours after ProHance administration.