Document
DailyMed Label: LumaSon
Title
DailyMed Label: LumaSon
Date
2023
Document type
DailyMed Prescription
Name
LumaSon
Generic name
SULFUR HEXAFLUORIDE
Manufacturer
BRACCO DIAGNOSTICS INC
Product information
NDC: 0270-7097
Product information
NDC: 0270-7099
Product information
NDC: 0270-7099
Product information
NDC: 0270-7097
Product information
NDC: 0270-7097
Product information
NDC: 0270-7099
Product information
NDC: 0270-7097
Product information
NDC: 0270-7099
Product information
NDC: 0270-7099
Product information
NDC: 0270-7097
Product information
NDC: 0270-7099
Product information
NDC: 0270-7099
Product information
NDC: 0270-7097
Product information
NDC: 0270-7097
Description
Lumason (sulfur hexafluoride lipid-type
A microspheres) for injectable suspension, for intravenous or intravesical
use is used to prepare the ultrasound contrast agent. Lumason is supplied
in two presentations (single patient use kit or 20-vial pack):
The single patient use kit contains the following three
items:
one clear glass 10 mL vial containing 25 mg of white lyophilized
powder lipid-type A, 60.7 mg of sulfur hexafluoride gas and capped
with a blue flip-cap
one prefilled syringe containing 5 mL 0.9% Sodium Chloride
Injection, USP (Diluent) Each prefilled syringe with 5
mL of diluent 0.9% Sodium Chloride Injection, USP is sterile, nonpyrogenic,
and additive-free containing 9 mg sodium chloride per mL.
one Mini-Spike
The 20-vial pack is comprised of:
twenty Lumason clear vials, each containing 25 mg of lipid-type
A sterile white lyophilized powder with headspace filled with 60.7
mg of sulfur hexafluoride gas
twenty Mini-Spikes
twenty peel-off syringe labels
Each vial is formulated
as a 25 mg sterile, pyrogen-free lyophilized powder containing 24.56
mg of polyethylene glycol 4000, 0.19 mg of distearoylphosphatidyl-choline
(DSPC), 0.19 mg of dipalmitoylphosphatidylglycerol sodium (DPPG-Na)
and 0.04 mg of palmitic acid. The headspace of each vial contains
6.07 mg/mL (± 2 %) sulfur hexafluoride, SF 6 , or 60.7 mg per vial.
Upon reconstitution with 5mL diluent, Lumason is a milky white, homogeneous
suspension containing sulfur hexafluoride lipid-type A microspheres.
The suspension is isotonic and has a pH of 4.5 to 7.5.
The sulfur hexafluoride lipid
microspheres are composed of SF 6 gas in the
core surrounded by an outer shell monolayer of phospholipids consisting
DSPC and DPPG-Na with palmitic acid as a stabilizer.
Sulfur hexafluoride has a molecular weight
of 145.9 and the following chemical structure:
1,2-Di s tearoyl- sn- glycero-3-phosphocholine (DSPC), with empirical formula C 44 H 88 NO 8 P, has a molecular weight of 790.6 and the following chemical structure:
1,2-Dipalmitoyl- sn -glycero-3-phospho- rac -glycerol sodium (DPPG-Na), with empirical formula C 38 H 74 NaO 10 P, has a molecular
weight of 745 and the following chemical structure:
Each milliliter of reconstituted Lumason suspension contains 1.5
to 5.6 x10 8 microspheres, 68 mcg SF 6 (12 mcL), 0.038 mg DSPC, 0.038 mg DPPG-Na, 4.91 mg
polyethylene glycol 4000 and 0.008 mg palmitic acid. The sulphur hexafluoride
associated with the microspheres suspension is 45 mcg/mL. Fifteen
to twenty three percent of the total lipids in the suspension are
associated with the microspheres.
The sulfur hexafluoride lipid microsphere
characteristics are listed in Table 2:
Table 2. Microsphere Characteristics
Mean diameter range
1.5 – 2.5 μm
Percent of microspheres
≤ 10 µm
≥ 99%
Upper size limit
100.0% ≤ 20 µm
sulfur-hexafluoride-chemical-structure
empirical-formula-790-6
empirical-formula-745
Indications
Echocardiography
Lumason is indicated
for use in adult and pediatric patients with suboptimal echocardiograms
to opacify the left ventricular chamber and to improve the delineation
of the left ventricular endocardial border.
Ultrasonography of the Liver
Lumason is indicated
for use with ultrasound of the liver in adult and pediatric patients
to characterize focal liver lesions.
Ultrasonography of the Urinary
Tract
Lumason
is indicated for use in ultrasonography of the urinary tract in pediatric
patients for the evaluation of suspected or known vesicoureteral reflux.
Lumason is an ultrasound contrast
agent indicated for use
in echocardiography to opacify the left ventricular chamber
and to improve the delineation of the left ventricular endocardial
border in adult and pediatric patients with suboptimal echocardiograms
( 1 )
in ultrasonography of the liver for characterization of
focal liver lesions in adult and pediatric patients ( 1 )
in ultrasonography of the urinary tract for the evaluation
of suspected or known vesicoureteral reflux in pediatric patients
( 1 )
Dosage
Avoid intra-arterial injection ( 2.1 , 5.3 )
See Full Prescribing Information for reconstitution instructions ( 2.3 )
For intravenous injection :
Echocardiography in adults: After reconstitution, administer 2 mL as an intravenous injection ( 2.2 , 2.4 )
Echocardiography in pediatric patients: After reconstitution, administer 0.03 mL per kg as an intravenous injection up to a maximum of 2 mL per injection ( 2.2 , 2.4 )
Ultrasonography of the liver in adults: After reconstitution, administer 2.4 mL as an intravenous injection ( 2.2 , 2.4 )
Ultrasonography of the liver in pediatric patients: After reconstitution, administer 0.03 mL per kg as an intravenous injection, up to a maximum of 2.4 mL per injection ( 2.2 , 2.4 )
May repeat dose one time during a single examination ( 2.2 , 2.4 )
Follow each injection with an intravenous flush of 0.9% Sodium Chloride Injection, USP ( 2.2 , 2.4 )
For intravesical administration in pediatric patients :
Ultrasonography of the urinary tract: After reconstitution, administer 1 mL via sterile 6 to 8F urinary catheter. Bladder should be first emptied and then partially filled with 0.9% Sodium Chloride Injection, USP before injection of Lumason ( 2.2 , 2.4 )
After Lumason administration, continue filling the bladder with 0.9% Sodium Chloride Injection, USP until the patient has the urge to micturate or at the first sign of back pressure to the infusion ( 2.4 )
Do not administer Lumason by intra-arterial injection [see
Warnings and Precautions ( 5.3 )] .
Echocardiography
Adults
The recommended dose
of Lumason after reconstitution is 2 mL administered as an intravenous
bolus injection during echocardiography. During a single examination,
a second injection of 2 mL may be administered to prolong contrast
enhancement. Follow each Lumason injection with an intravenous flush
using 5 mL of 0.9% Sodium Chloride Injection, USP.
Pediatric Patients
The recommended dose of Lumason
after reconstitution in pediatric patients is 0.03 mL per kg administered
as an intravenous injection during echocardiography. During a single
examination, a second injection of 0.03 mL per kg may be administered,
if needed. Do not exceed 2 mL per injection. Follow Lumason injection
with an intravenous flush using 5 mL of 0.9% Sodium Chloride Injection,
USP.
Ultrasonography
of the Liver
Adults
The recommended dose of Lumason after reconstitution in adult patients
is 2.4 mL administered as an intravenous injection during ultrasonography
of the liver. During a single examination, a second injection of
2.4 mL may be administered, if needed. Follow Lumason injection with
an intravenous flush using 5 mL of 0.9% Sodium Chloride Injection,
USP.
Pediatric
Patients
The
recommended dose of Lumason after reconstitution in pediatric patients
is 0.03 mL per kg administered as an intravenous injection during
ultrasonography of the liver. During a single examination, a second
injection of 0.03 mL per kg may be administered, if needed. Do not
exceed 2.4 mL per injection. Follow Lumason injection with an intravenous
flush of 0.9% Sodium Chloride Injection, USP.
Ultrasonography of the Urinary
Tract
Pediatric Patients
The recommended dose of Lumason after
reconstitution is 1 mL. The bladder may be refilled with 0.9% Sodium
Chloride Injection, USP for a second cycle of voiding and imaging,
without the need of a second Lumason administration.
Refer to Section 2.3.1 for instructions for using the single
patient use kit with diluent provided
Refer to Section 2.3.2 for instructions for using the 20-vial
pack without diluent provided
Contents of Lumason Kit
Inspect the Lumason kit and its components for signs of
damage. Do not use the kit if the protective caps on the Lumason
vial and prefilled syringe with 5 mL 0.9% Sodium Chloride Injection,
USP are not intact or if the kit shows other signs of damage.
Under aseptic conditions, reconstitute the Lumason vial
using the following illustrated steps:
1. Connect the plunger rod
to the prefilled 0.9% Sodium Chloride Injection, USP syringe barrel
by screwing it clockwise into the syringe (see Figure 1).
2. Open the Mini-Spike blister and remove the syringe tip cap (see
Figure 2).
3. Remove the Mini-Spike green cap and connect
the syringe to the Mini-Spike by screwing it in clockwise (see Figure
3).
4. Remove the Mini-Spike spike protection and position the spike
in the center of the rubber stopper of the vial. Press firmly inward
until the spike is fully inserted in the stopper (see Figure 4).
5. Empty the content of the syringe into the vial by pushing on the
plunger rod (see Figure 5).
6. Shake vigorously for 20 seconds, mixing
all the contents in the vial (see Figure 6). A homogeneous white milky
liquid indicates formation of sulfur hexafluoride lipid microspheres.
7. For preparation of doses greater than or equal to 1 mL, invert
the system and slowly withdraw the intended volume of suspension into
the syringe (see Figure 7). For preparation of doses less than 1 mL,
withdraw 2 mL of the reconstituted suspension into the 5 mL syringe
and measure the volume of Lumason to inject by using the 0.2 mL graduations
between the 1 mL and 2 mL marks.
8. Unscrew the syringe from the Mini-Spike (see Figure 8). Peel and
remove the diluent label to display the reconstituted product label.
For intravenous administration, immediately connect the syringe to
a dose administration line (20 G) and administer as directed under
the Administration Instructions below. For intravesical administration,
immediately connect the syringe to a sterile urinary catheter (6 French
to 8 French) and administer as directed under the Administration Instructions
below.
Following reconstitution, Lumason suspension contains 1.5
to 5.6 x10 8 microspheres/mL with 45 mcg/mL
of sulfur hexafluoride.
Use immediately after reconstitution. If the suspension
is not used immediately after reconstitution, resuspend the microspheres
for a few seconds by hand agitation before the suspension is drawn
into the syringe. Reconstituted suspension within a vial may be used
for up to 3 hours from the time of its reconstitution. Maintain the
vial containing the reconstituted suspension at room temperature 25°C
(77°F); excursions permitted to 15° to 30°C (59° to 86°F).
glass-vial-spike-syringe-and-rod
figure 1
figure 2
figure 3
figure 4
figure 5
figure 6
figure 7
figure 8
Contents of Lumason Pack
*Please note: This presentation
does not include pre-filled syringes of 0.9% Sodium Chloride Injection,
USP (Diluent).
Lumason
vials are to be used with the supplied Mini-Spike only.
Use only additive-free
0.9% Sodium Chloride Injection, USP for the reconstitution of Lumason.
Reconstitution
Inspect the Lumason components for signs of damage. Do not
use the Lumason vial if the protective cap on the vial is not intact
or other components in the pack show signs of damage.
Use aseptic conditions for the preparation and administration
of Lumason.
1. Obtain a 5 mL syringe,
with luer lock tip, and fill with 5 mL of additive-free 0.9% Sodium
Chloride Injection, USP (diluent) (see Figure 1).
Two healthcare professionals (HCPs) should verify that the
solution selected for reconstitution of Lumason is additive-free 0.9%
Sodium Chloride Injection, USP.
Ensure that any air in the syringe is expelled.
[Note: A prefilled syringe containing additive-free 0.9% Sodium Chloride
Injection, USP may be used. Ensure that any air in the syringe is
expelled.]
2. Remove
the Mini-Spike green cap and connect the syringe to the Mini-Spike
by screwing it in clockwise (see Figure 2).
3. Remove the Mini-Spike spike protection and position the spike
in the center of the rubber stopper of the vial. Press firmly inward
until the spike is fully inserted in the stopper (see Figure 3).
4. Empty the entire 5 mL content of the syringe into the vial by
pushing on the plunger rod (see Figure 4).
5. Shake vigorously for 20 seconds, mixing all the contents in the
vial (see Figure 5). A homogeneous white milky liquid indicates formation
of sulfur hexafluoride lipid microspheres.
6. To obtain required dose, invert the system and slowly withdraw
the intended volume of suspension into the syringe (see Figure 6).
7. Unscrew the syringe from the Mini-Spike (see Figure 7).
8. Label the syringe using the peel-off sticker provided.
9. For intravenous administration,
immediately connect the syringe to a dose administration line (20G)
and administer as directed under the Administration Instructions below.
For intravesical administration, immediately connect the syringe
to a sterile urinary catheter (6 French to 8 French) and administer
as directed under the Administration Instructions below.
Following reconstitution, Lumason suspension contains 1.5
to 5.6 x10 8 microspheres/mL with 45 mcg/mL
of sulfur hexafluoride.
Use immediately after reconstitution. If the suspension
is not used immediately after reconstitution, resuspend the microspheres
for a few seconds by hand agitation before the suspension is drawn
into the syringe. Reconstituted suspension within a vial may
be used for up to 3 hours from the time of its reconstitution. Maintain
the vial containing the reconstituted suspension at room temperature
25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
glass vial spike labels figure
figure 1
figure 2
figure 3
figure 4
figure 5
figure 6
figure 7
Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted suspension is milky-white, and does not contain visible particulate matter. Do not use the single-patient use vial for more than one patient.
Intravenous Administration
Administer Lumason as an intravenous bolus injection.
Intravesical Administration in Pediatric Patients
Insert a sterile 6 French to 8 French urinary catheter into the bladder under sterile conditions;
Empty the bladder of urine, and then fill the bladder with sterile 0.9% Sodium Chloride Injection, USP to approximately one third or half of its predicted total volume. The total bladder volume in children is calculated as [(age in years + 2) x 30] mL;
Administer Lumason as an intravesical bolus injection through the urinary catheter;
Continue filling the bladder with 0.9% Sodium Chloride Injection, USP until the patient has the urge to micturate or at the first sign of back pressure to the infusion.
Immediately following the first voiding, the bladder may be refilled with 0.9% Sodium Chloride Injection, USP for a second cycle of voiding and imaging, without the need of a second Lumason administration.
Echocardiography
After baseline non-contrast
echocardiography is complete, adjust the mechanical index for the
ultrasound device to 0.8 or lower. Continue ultrasound imaging following
Lumason injection.
Ultrasonography of the Liver
After identification of the target focal
lesion on non-contrast ultrasound examination, hold transducer still
while switching scanner to low mechanical index (≤ 0.4) contrast-specific
imaging. Continue ultrasound imaging following Lumason injection.
Ultrasonography of
the Urinary Tract
After baseline non-contrast ultrasound examination
of the kidney and bladder, switch the scanner to low mechanical index
(≤0.4) contrast specific imaging. Perform continuous alternate ultrasound
imaging of the bladder, ureters, and kidneys during filling and voiding
of the bladder.
Dosage forms
For injectable suspension: Lumason
is supplied in two presentations (single patient use kit or 20-vial
pack):
3-part single
patient use kit comprised of:
one Lumason clear vial containing 25 mg of lipid-type A
sterile white lyophilized powder with headspace filled with 60.7 mg
of sulfur hexafluoride gas
one prefilled syringe containing 5 mL of 0.9% Sodium Chloride
Injection, USP (Diluent)
one Mini-Spike
20-vial pack comprised
of:
twenty Lumason clear vials, each containing 25 mg of lipid-type
A sterile white lyophilized powder with headspace filled with 60.7
mg of sulfur hexafluoride gas
twenty Mini-Spikes
twenty peel-off syringe labels
Following reconstitution,
Lumason is a homogeneous, milky white suspension containing 1.5 to
5.6 x 10 8 microspheres/mL with 45 mcg/mL
of sulfur hexafluoride.
For injectable suspension: 25 mg of lipid-type A lyophilized
powder with headspace fill of 60.7 mg sulfur hexafluoride in a single-patient
use vial for reconstitution ( 3 )
Contraindications
Lumason is contraindicated in patients with
known or suspected:
Hypersensitivity to sulfur hexafluoride lipid microsphere
or its components, such as polyethylene glycol (PEG) [see
Warnings and Precautions ( 5.2 ) and
Description ( 11 )] .
Hypersensitivity to sulfur hexafluoride lipid microspheres
or its components, such as polyethylene glycol (PEG) ( 4 )
Warnings
Cardiopulmonary reactions, including fatalities. Always
have resuscitation equipment and trained personnel readily available
( 5.1 )
Hypersensitivity reactions. Serious acute hypersensitivity
reactions have occurred in patients with no prior exposure to sulfur
hexafluoride lipid-containing microsphere products, including patients
with prior hypersensitivity reaction(s) to PEG ( 5.2 , 6 )
Serious cardiopulmonary reactions, including fatalities have occurred
uncommonly during or shortly following administration of ultrasound
contrast agents, including Lumason. These reactions typically occurred
within 30 minutes of administration. The risk for these reactions
may be increased among patients with unstable cardiopulmonary conditions
(acute myocardial infarction, acute coronary artery syndromes, worsening
or unstable congestive heart failure, or serious ventricular arrhythmias).
Always have cardiopulmonary resuscitation personnel and equipment
readily available prior to Lumason administration and monitor all
patients for acute reactions.
The reported reactions that may follow the
administration of ultrasound contrast agents include: fatal cardiac
or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial
fibrillation, tachycardia, bradycardia, supraventricular tachycardia,
ventricular fibrillation, and ventricular tachycardia), hypertension,
hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor,
wheezing, loss of consciousness, and convulsions.
In postmarketing use, serious hypersensitivity reactions were observed
during or shortly following sulfur hexafluoride lipid-containing microsphere
administration including:
Anaphylaxis, with manifestations that may
include death, shock, bronchospasm, dyspnea, throat tightness, angioedema,
edema (pharyngeal, palatal, mouth, peripheral, localized), swelling
(face, eye, lip, tongue, upper airway), facial hypoesthesia, rash,
urticaria, pruritus, flushing, and erythema.
These reactions may occur in patients with
no history of prior exposure to sulfur hexafluoride lipid-containing
microspheres. Lumason contains PEG. There may be increased risk of
serious reactions including death in patients with prior hypersensitivity
reaction(s) to PEG [see Adverse Reactions ( 6.2 )] . Clinically assess patients
for prior hypersensitivity reactions to products containing PEG, such
as certain colonoscopy bowel preparations and laxatives. Always have
cardiopulmonary resuscitation personnel and equipment readily available
prior to Lumason administration and monitor all patients for hypersensitivity
reactions.
When administering Lumason to
patients with cardiac shunt, microspheres can bypass filtering by
the lung and enter the arterial circulation. Assess patients with
shunts for embolic phenomena following Lumason administration. Lumason
is only for intravenous and/or intravesical administration; do not
administer Lumason by intra-arterial injection [see Dosage
and Administration ( 2.1 )].
High ultrasound mechanical index
values may cause microsphere cavitation or rupture and lead to ventricular
arrhythmias. Additionally, end-systolic triggering with high mechanical
indices has been reported to cause ventricular arrhythmias.
Lumason is not recommended for
use at mechanical indices greater than 0.8.
Adverse reactions
The following serious adverse reactions are
discussed elsewhere in the labeling:
Use in_specific_populations
Risk Summary
There are no data with Lumason use in pregnant
women to inform any drug-associated risks. No adverse developmental
outcomes were observed in animal reproduction studies with administration
of sulfur hexafluoride lipid-type A microspheres in pregnant rats
and rabbits during organogenesis at doses up to at least 10 and 20
times, respectively, the maximum human dose of 4.8 mL based on body
surface area ( see Data
).
In the U.S. general population,
the estimated background risk of major birth defects and miscarriage
in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Lumason was administered intravenously
to rats at doses of 0.2, 1, and 5 mL/kg (approximately 0.4, 2, and
10 times the recommended maximum human dose of 4.8 mL, respectively,
based on body surface area); Lumason doses were administered daily
for about 30 consecutive days, from two weeks before pairing until
the end of organogenesis. Lumason was administered intravenously to
rabbits at doses of 0.2, 1, and 5 mL/kg (approximately 0.8, 4, and
20 times the recommended maximum human dose, respectively, based on
body surface area); Lumason doses were administered daily from gestation
day 6 to day 19 inclusive. No significant findings on the fetus were
observed.
Risk Summary
There are no data
on the presence of Lumason in human milk, the effects on the breastfed
infant, or the effects on milk production. The developmental and health
benefits of breastfeeding should be considered along with the mother’s
clinical need for Lumason and any potential adverse effects on the
breastfed infant from Lumason or from the underlying maternal condition.
Echocardiography
Safety and effectiveness
have been established for use in pediatric patients with suboptimal
echocardiograms to opacify the left ventricular chamber and to improve
delineation of the left endocardial border. Safety and effectiveness
in pediatric patients are based on adequate and well-controlled studies
in adults and are supported by a clinical study in 12 pediatric patients
(mean age: 13.8 years) with extrapolation of efficacy to younger pediatric
patients. No new adverse reactions were reported in the pediatric
study [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 )] . Safety of intravenous use of Lumason was based on evaluation of
published literature involving the use of Lumason in over 1400 pediatric
patients (0 to 17 years).
Ultrasonography of the Liver
Safety and effectiveness in pediatric patients
has been established for use in ultrasonography of the liver for characterization
of focal liver lesions from adequate and well controlled trials in
adult patients and a clinical study of 44 pediatric patients [see Clinical Studies ( 14 )] . Safety of intravenous use of Lumason was based on evaluation of
published literature involving use of Lumason in over 1400 pediatric
patients. Non-fatal anaphylaxis was reported in one pediatric patient.
Ultrasonography of
the Urinary Tract
Safety and effectiveness in pediatric patients
has been established for use in ultrasonography of the urinary tract
for the evaluation of suspected or known vesicoureteral reflux from
two published studies comprising a total of 411 pediatric patients [see Clinical Studies ( 14 )] . Safety of intravesical use of Lumason was based on evaluation of
published literature involving use of Lumason in over 6000 pediatric
patients. No adverse reactions were reported.
Of the total number of 6856 adult patients
in clinical studies of Lumason, 39% were 65 and over, while 11% were
75 and older. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between
the elderly or younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
How supplied
Lumason (sulfur hexafluoride lipid-type A microspheres) for injectable suspension is supplied as a single patient use kit and as a 20-vial pack as follows:
5 single patient use kits (NDC 0270-7099-73) with each kit containing:
One Lumason vial of 25 mg lipid-type A white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluoride
One prefilled syringe containing 5mL of 0.9% Sodium Chloride Injection, USP (Diluent)
One Mini-Spike
Each kit is packaged in a clear plastic container.
20-vial pack (NDC 0270-7097-08) containing:
Twenty (20) Lumason vials of 25 mg lipid-type A white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluoride
Twenty (20) Mini-Spikes
Twenty (20) peel-off syringe labels
Store the kit at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Clinical pharmacology
Within the blood, the acoustic impedance
of Lumason microspheres is lower than that of the surrounding non-aqueous
tissue. Therefore, an ultrasound beam is reflected from the interface
between the microspheres and the surrounding tissue. The reflected
ultrasound signal provides a visual image that shows a contrast between
the blood and the surrounding tissues.
For ultrasonography of the urinary tract
in pediatric patients, the intravesically administered Lumason microspheres
increase signal intensity of fluids within the urethra, bladder, ureters,
and renal pelvis.
Lumason provides useful echocardiographic
signal intensity for two minutes after intravenous injection. Lumason
microspheres are destroyed and contrast enhancement decreases as the
mechanical index increases (values of 0.8 or less are recommended).
For ultrasonography of the liver,
Lumason provides dynamic patterns of differential signal intensity
enhancement between focal liver lesions and liver parenchyma during
the arterial, portal venous, and late phase of signal intensity enhancement
of the microvasculature.
In ultrasonography of the urinary tract, Lumason facilitates the
detection of reflux of fluid from the bladder into the ureters.
Pulmonary Hemodynamic
Effects
The
effect of Lumason on pulmonary hemodynamics was studied in a prospective,
open-label study of 36 patients scheduled for right heart catheterization,
including 18 with mean pulmonary arterial pressure (MPAP) > 25 mmHg
and 18 with MPAP ≤ 25 mmHg. No clinically important pulmonary hemodynamic
changes were observed. This study did not assess the effect of Lumason
on visualization of cardiac or pulmonary structures.
The pharmacokinetic of the SF 6 gas component of Lumason was evaluated in 12 healthy adult subjects.
After intravenous bolus injections of 0.03 mL/kg and 0.3 mL/kg of
Lumason, corresponding to approximately 1 and 10 times the recommended
doses, concentrations of SF 6 in blood peaked
within 1 to 2 minutes for both doses. The terminal half-life of SF 6 in blood was approximately 10 minutes for the 0.3 mL/kg
dose. The area-under-the-curve of SF 6 was
dose-proportional over the dose range studied.
Distribution
In a study of healthy subjects,
the mean values for the apparent steady-state volume of distribution
of SF 6 following intravenous administration,
were 341 mcL and 710 mcL for Lumason doses of 0.03 mL/kg and 0.3 mL/kg,
respectively. Preferential distribution to the lung is likely responsible
for these values.
Elimination
Following intravenous administration, the SF 6 component of Lumason is eliminated via the lungs. In a clinical
study that examined SF 6 elimination twenty
minutes following Lumason injection, the mean cumulative recovery
of SF 6 in expired air was 82 ± 20% (SD) at
the 0.03 mL/kg dose and 88 ± 26% (SD) at the 0.3 mL/kg dose.
SF 6 undergoes
first pass elimination within the pulmonary circulation; approximately
40% to 50% of the SF 6 content was eliminated
in the expired air during the first minute following Lumason injection.
Metabolism
SF 6 undergoes little or no biotransformation; following intravenous
administration, 88% of an administered dose is recovered unchanged
in expired air.
Pharmacokinetics in Specific Populations
Pulmonary Impairment:
In a study of patients with pulmonary
impairment, blood concentrations of SF 6 peaked
at 1 to 4 minutes following intravenous Lumason administration. The cumulative
recovery of SF 6 in expired air was 102 ± 18%
(mean ± standard deviation), and the terminal half-life of SF 6 in blood was similar to that measured in healthy subjects.
Nonclinical toxicology
No long-term animal studies were
performed to evaluate the carcinogenic potential of Lumason. No evidence
of genotoxicity was found in the following studies conducted with
Lumason: 1) a bacterial mutagenesis (Ames) assay, 2) an in vitro human
lymphocyte chromosome aberration assay, and 3) an in vivo mouse micronucleus
assay.
No impairment
of fertility was observed in rats receiving Lumason at doses up to
8 times the human dose based on body surface area.
Clinical studies
Adults
A total of 191 patients with
suspected cardiac disease and suboptimal non-contrast echocardiography
received Lumason in three multi-center controlled clinical trials
(76 patients in Study A, 62 patients in Study B, and 53 patients in
Study C). Among these patients, there were 127 men and 64 women. The
mean age was 59 years (range 22 to 96 years). The racial and ethnic
representations were 79% White, 16% Black, 4% Hispanic, < 1% Asian,
and < 1% other racial or ethnic groups. The mean weight was 204
lbs (range 92 to 405 lbs). Approximately 20% of the patients had a
chronic pulmonary disorder and 30% had a history of heart failure.
Of the 106 patients for whom a New York Heart Association (NYHA) classification
of heart failure was assigned, 49% were Class I, 33% were Class II,
and 18% were Class III. Patients with NYHA Class IV heart failure
were not included in these studies.
In Studies A and B, each patient received
four intravenous bolus injections of Lumason (0.5, 1, 2, and 4 mL),
in randomized order. In Study C, each patient received two doses of
Lumason (1 mL and 2 mL) in randomized order. All three studies assessed
endocardial border delineation and left ventricular opacification.
For each patient in each study, echocardiography with Lumason was
compared to non-contrast (baseline) echocardiography. A recording
of 2D echocardiography was obtained from 30 seconds prior to each
injection to at least 15 minutes after dosing or until the disappearance
of the contrast effect, whichever was longer. Contrast and non-contrast
echocardiographic images for each patient were evaluated by two independent
reviewers, who were blinded to clinical information and the Lumason
dose. Evaluation of left ventricular endocardial border consisted
of segment based assessment involving six endocardial segments and
using two apical views (2- and 4-chamber views).
Endocardial Border Delineation
and Duration of Useful Contrast Effect
In all three studies, administration of Lumason
improved left ventricular endocardial border delineation. The majority
of the patients who received a 2.0 mL dose of Lumason had improvement
in endocardial border delineation manifested as visualization of at
least two additional endocardial border segments. Table 3 demonstrates
the improvement in endocardial border delineation following Lumason
administration as a reduction in percentage of patients with inadequate
border delineation in at least one pair of adjacent segments (combined
2-chamber and 4-chamber view). The results are shown by reader.
Table 3. Reduction in Percentage of Patients with Inadequate Border
Delineation
Reader
Study
A N = 76
Study
B N = 62
Study
C N = 53
Non- contrast
Lumason
Non- contrast
Lumason
Non- contrast
Lumason
A
60 (79%)
22 (33%)
31 (50%)
12 (19%)
12 (23%)
10 (19%)
B
62 (82%)
29 (37%)
54 (87%)
6 (10%)
45 (85%)
20 (38%)
Following the first appearance
of contrast within the left ventricle the mean duration of useful
contrast effect ranged from 1.7 to 3.1 minutes.
Left Ventricular Opacification
In all three studies,
complete left ventricular opacification was observed in 52% to 80%
of the patients following administration of a 2.0 mL dose of Lumason.
The studies did not sufficiently assess the effect of Lumason upon
measures of left ventricular ejection fraction and wall motion.
Pediatric patients:
Twelve pediatric
patients 9 to 17 years of age with suspected cardiac disease and suboptimal
non-contrast echocardiography received Lumason in one prospective
multicenter clinical trial. Patients received Lumason at a dose of
0.03 mL/kg (mean 1.83 mL). There were 7 female, 10 white, and 2 black
patients.
For both
the non-contrast and contrast-enhanced images, standard apical 4-,
2-, and 3- chamber views with harmonic imaging were acquired. Contrast
and non-contrast images for each patient were evaluated by three independent
reviewers, who were blinded to clinical information.
Endocardial Border Delineation
Evaluation of
left ventricular endocardial border delineation consisted of segment-based
assessment of the left ventricle divided into 17 endocardial segments.
The delineation of each segment’s endocardial border was rated as
inadequate, sufficient, or good. An exam was considered suboptimal
if any of the patient’s apical views had 2 or more adjacent segments
with inadequate delineation scores.
The majority of screened patients had adequate
delineation of the left ventricular endocardial border without administration
of contrast. The number of patients with inadequate left ventricular
endocardial border delineation without contrast and after Lumason
are shown for the 12 patients, by reader, in Table 4.
a Reader A had missing
segment data with contrast echocardiography for one patient;
b Reader B had missing segment data with
non-contrast echocardiography for one patient;
bb Reader B had missing segment data with contrast
echocardiography for three patients;
c Reader C had missing segment data with contrast echocardiography
for one patient
Table 4. Number of Pediatric Patients with Inadequate Border Delineation
with and without Lumason
Reader A
Reader B
Reader C
Non-contrast
12/12
11/11 b
12/12
Lumason
1/11 a
0/9 bb
0/11 c
Left Ventricular
Opacification
Complete left ventricular opacification
was observed in all the patients by all 3 readers following administration
of Lumason.
Adults
A total of 499 patients with at least 1 focal liver lesion requiring
characterization were evaluated in two studies (259 patients in Study
A, 240 patients in Study B). Among these patients, there were 259
men and 240 women. The mean age was 56 years (range 19 to 93 years).
The racial and ethnic representations were 74% White, 11% Black, 9%
Hispanic, 5% Asian, and 1% other racial or ethnic groups. The mean
weight was 80 kg (range 44 to 173 kg).
In both studies, prior to Lumason administration,
gray scale and Doppler (color or power imaging) ultrasound examinations
of the target lesion were performed using commercially available ultrasound
equipment and using standard techniques. Each patient received an
intravenous injection of 2.4 mL of Lumason (up to 2 injections were
allowed, 91% patients received 1 injection). Following Lumason administration,
ultrasound examination of the target lesion was carried out using
contrast-specific imaging modes operating at MI ≤ 0.4. The probe was
positioned to provide optimal visualization over the target lesion
and was kept in the same position for at least 180 seconds.
Truth standard included: histology/surgery,
contrast CT, contrast MRI, and/or 6 month follow-up.
For each study, the interpretation of images
was conducted by three independent readers who were blinded to clinical
data. Lesions were characterized as malignant or benign. Separate
blinded readers assessed the truth standard images.
Results of both studies demonstrated an improvement
in characterization of focal liver lesions using Lumason ultrasound
compared to non-contrast ultrasound images. Table 5 summarizes the
efficacy results by reader.
* Statistically significant
improvement from non-contrast (p<0.05 based on McNemar’s test)
Table 5. Diagnostic Performance of Lumason Ultrasound for Characterization
of Focal Liver Lesions
Study
A:
Sensitivity
(patients with malignant lesions) N=119
Specificity
(patients with benign lesions) N=140
Lumason %
Non-contrast %
Difference (95%
CI)
Lumason %
Non-contrast %
Difference (95%
CI)
Reader 1
87*
49
38 (30, 54)
71
63
8 (-4, 21)
Reader 2
76*
35
41 (29, 52)
83*
54
29 (21, 44)
Reader 3
92*
16
76 (67, 84)
73*
22
51 (40, 61)
Study
B:
Sensitivity
(patients with malignant lesions) N=124
Specificity
(patients with benign lesions) N=116
Lumason %
Non-contrast %
Difference (95%
CI)
Lumason %
Non-contrast %
Difference (95%
CI)
Reader 4
65
53
12 (-1, 23)
72*
24
48 (35, 58)
Reader 5
61*
41
20 (7, 32)
67*
7
60 (50, 70)
Reader 6
47
66
-19 (-31, -7)
88*
59
29 (18, 40)
Pediatric patients
In one published
study, 44 patients with an indeterminate focal liver lesion (23 males,
21 females, age range: 4-18 years, median 11.5 years) were evaluated
after intravenous bolus administration of 1.2 to 2.4 mL of Lumason.
The findings of Lumason ultrasound images were compared to CT, MRI
or histology. Specificity was 98% (43/44 patients).
Pediatric Patients
The efficacy of Lumason for the
evaluation of pediatric patients with suspected or known vesicoureteral
reflux was established in two published open-label single center studies
(A and B). Patients received 1 mL of Lumason intravesically and underwent
voiding urosonography (VUS). Patients were also evaluated with voiding
cystourethrography (VCUG) as the reference standard. The presence
or absence of urinary reflux with Lumason ultrasound was compared
to the radiographic reference standard.
Study A evaluated 183 patients (94 male, 89
female; age 2 days - 44 months) with a total of 366 kidney-ureter
units. The images were interpreted by one on-site reader, blinded
to the reference standard. Out of 103 reference standard-positive
images, Lumason VUS was positive in 89 units and falsely negative
in 14 units. In 263 units with negative reference standard, the Lumason
ultrasonography was negative in 226 and falsely positive in 37.
Study B evaluated 228 patients
(123 male, 105 female; age 6 days -13 years) with a total of 463 kidney-ureter
units (some patients had more than 2 units). The images were interpreted
independently by two on-site readers, blinded to the reference standard.
Out of 71 reference standard positive images, Lumason ultrasonography
was positive in 57 and falsely negative in 14. In 392 units with negative
reference standard, Lumason ultrasonography was negative in 302 and
falsely positive in 90.
Package label
Lumason
- KIT Box Label NDC: 0270-7099-73
NovaPlus KIT - BOX LAB (CF108405)
1 organization
2 products
Product
LumasonProduct
Sulfur HexafluorideOrganization
Bracco Diagnostics Inc