NDC 0270-7097 Lumason

Sulfur Hexafluoride

NDC Product Code 0270-7097

NDC 0270-7097-07

Package Description: 20 VIAL in 1 BOX > 25 mg in 1 VIAL

NDC 0270-7097-08

Package Description: 20 VIAL in 1 BOX > 25 mg in 1 VIAL

NDC Product Information

Lumason with NDC 0270-7097 is a a human prescription drug product labeled by Bracco Diagnostics Inc. The generic name of Lumason is sulfur hexafluoride. The product's dosage form is injection, powder, lyophilized, for suspension and is administered via intravenous; intravesical form.

Labeler Name: Bracco Diagnostics Inc

Dosage Form: Injection, Powder, Lyophilized, For Suspension - A liquid preparation, intended for parenteral use that contains solids suspended in a suitable fluid medium and conforms in all respects to the requirements for Sterile Suspensions; the medicinal agents intended for the suspension are prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Lumason Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • SULFUR HEXAFLUORIDE 60.7 mg/mg
  • DISTEAROYLPHOSPHATIDYLCHOLINE, DL- .19 mg/mg
  • SODIUM 1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHO-(1'-RAC-GLYCEROL) .19 mg/mg
  • SULFUR HEXAFLUORIDE 60.7 mg/mg
  • DISTEAROYLPHOSPHATIDYLCHOLINE, DL- .19 mg/mg
  • SODIUM 1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHO-(1'-RAC-GLYCEROL) .19 mg/mg

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravesical - Administration within the bladder.
  • Intravenous - Administration within or into a vein or veins.
  • Intravesical - Administration within the bladder.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Contrast Agent for Ultrasound Imaging - [EPC] (Established Pharmacologic Class)
  • Ultrasound Contrast Activity - [MoA] (Mechanism of Action)
  • Contrast Agent for Ultrasound Imaging - [EPC] (Established Pharmacologic Class)
  • Ultrasound Contrast Activity - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Bracco Diagnostics Inc
Labeler Code: 0270
FDA Application Number: NDA203684 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-01-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Lumason Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Serious Cardiopulmonary Reactions

  • Serious cardiopulmonary reactions, including
  • Fatalities, have occurred uncommonly during or following the injection
  • Of ultrasound contrast agents, including sulfur hexafluoride lipid
  • Microspheres [see Warnings and Precautions (5.1)]. Most serious reactions occur
  • Within 30 minutes of administration [see Warnings and Precautions
  • (5.1)].Assess all patients for the presence of any condition
  • That precludes administration [see Contraindications (4)].Always have resuscitation equipment and trained personnel
  • Readily available [see Warnings and Precautions (5.1)].

1  Indications And Usage

EchocardiographyLumason 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 LiverLumason is indicated
for use with ultrasound of the liver in adult and pediatric patients
to characterize focal liver lesions.Ultrasonography of the Urinary
TractLumason
is indicated for use in ultrasonography of the urinary tract in pediatric
patients for the evaluation of suspected or known vesicoureteral reflux.

2.1  Important Administration Instructions

Do not administer Lumason by intra-arterial injection [see
Warnings and Precautions (5.3)].

2.2  Recommended Dosage

EchocardiographyAdultsThe 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.Pediatric PatientsThe 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.Ultrasonography of the LiverAdultsThe 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.Pediatric PatientsThe recommended dose of Lumason
after reconstitution in pediatric patients is 0.03 mL per kg administered
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.Ultrasonography of the Urinary TractPediatric PatientsThe recommended dose of Lumason
after reconstitution is 1 mL. The bladder may be refilled with normal
saline for a second cycle of voiding and imaging, without the need
of a second Lumason administration.

2.3  Reconstitution Instructions

  • Contents of Lumason
  • KitInspect 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 Sodium Chloride 0.9% Injection are
  • Not intact or if the kit shows other signs of damage.Under aseptic conditions, reconstitute Lumason by injecting
  • The prefilled syringe with 5 mL Sodium Chloride 0.9% Injection into
  • The Lumason vial using the following illustrated steps:1. Connect the plunger rod to the prefilled
  • 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. Open the Mini-Spike green cap and connect the syringe to the Mini-Spike
  • By screwing it in clockwise (see Figure 3).4. Remove the flip cap plastic protective
  • Cap from the vial, 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 x108 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.

2.4  Administration Instructions

  • 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 AdministrationAdminister Lumason
  • As an intravenous bolus injection.Intravesical Administration in
  • Pediatric PatientsInsert 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
  • Saline (sterile 0.9% sodium chloride solution) 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 saline 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 normal saline for a second cycle of voiding and imaging,
  • Without the need of a second Lumason administration

2.5  Imaging Guidelines

EchocardiographyAfter 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 LiverAfter 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 TractAfter 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.

3  Dosage Forms And Strengths

  • For injectable suspension: Lumason
  • Is supplied as a 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 gasone prefilled syringe containing 5 mL Sodium Chloride 0.9%
  • Injection, USP (Diluent)one Mini-SpikeFollowing reconstitution,
  • Lumason is a homogeneous, milky white suspension containing1.5 to
  • 5.6 x108 microspheres/ mL with 45 mcg/mL
  • Of sulfur hexafluoride.

4  Contraindications

  • Lumason is contraindicated in patients with:history of hypersensitivity reactions to sulfur hexafluoride
  • Lipid microsphere components or to any of the inactive ingredients
  • In Lumason

5.1  Serious Cardiopulmonary Reactions

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.

5.2  Hypersensitivity Reactions

Hypersensitivity reactions such as skin erythema, rash, urticaria,
flushing, throat tightness, dyspnea, or anaphylactic shock have uncommonly
been observed following the injection of Lumason. These reactions
may occur in patients with no history of prior exposure to sulfur
hexafluoride lipid containing microspheres. Always have cardiopulmonary
resuscitation personnel and equipment readily available prior to Lumason
administration and monitor all patients for hypersensitivity reactions.

5.3  Systemic Embolization

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.

6  Adverse Reactions

  • The following serious adverse reactions are
  • Discussed elsewhere in the labeling:Cardiopulmonary reactions [see Warnings and Precautions
  • (5.1)]Hypersensitivity reactions [see Warnings and Precautions
  • (5.2)]

6.1  Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice.AdultsIn completed clinical trials, a total of
6984 adult subjects (128 healthy volunteers and 6856 patients) received
Lumason at cumulative doses ranging from 0.2 to 161 mL (mean 9.8 mL).
Lumason was administered mainly as single or multiple injections;
however, some subjects received infusion dosing. The majority (75%)
of subjects received Lumason at cumulative doses of 10 mL or less.
There were 64% men and 36% women, with an average age of 59 years
(range 17 to 99 years). A total of 79% subjects were White; 4% were
Black; 16% were Asian; <1% were Hispanic; and <1% were in other
racial groups or race was not reported.In the clinical trials, serious adverse reactions
were observed in 2 subjects; one who experienced a hypersensitivity-
type rash and presyncope and another who experienced anaphylactic
shock shortly following Lumason administration.The most commonly reported adverse reactions
among patients (occurring among at least 0.2% of patients) are listed
below (Table 1). Most adverse reactions were mild to moderate in intensity
and resolved spontaneously.*occurring in at least 0.2% of patientsTable 1. Adverse Reactions in Adult Patients*n = 6856Number (%) of Patients with
Adverse Reactions340 (5%)Headache65 (1%)Nausea37 (0.5%)Dysgeusia29 (0.4%)Injection site pain23 (0.3%)Feeling Hot18 (0.3%)Chest discomfort17 (0.2%)Chest pain12 (0.2%)Dizziness11 (0.2%)Injection Site Warmth11 (0.2%)Pediatric PatientsIn completed clinical
trials for echocardiography, a total of 12 pediatric patients received
Lumason at a dose of 0.03 mL/kg. No adverse reactions were identified
in pediatric patients [see Clinical Studies (14.1)].

6.2  Postmarketing Experience

In the international postmarketing
clinical experience and clinical trials, serious adverse reactions
have uncommonly been reported following administration of Lumason.
Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
The serious adverse reactions include fatalities, especially in a
pattern of symptoms suggestive of anaphylactoid/hypersensitivity reactions.
Other serious reactions included arrhythmias and hypertensive episodes.
These reactions typically occurred within 30 minutes of Lumason administration.

8.1  Pregnancy

Risk SummaryThere 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.DataAnimal DataLumason 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.

8.2  Lactation

Risk SummaryThere 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.

8.4  Pediatric Use

EchocardiographySafety 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 LiverSafety 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 TractSafety 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.

8.5  Geriatric Use

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.

11  Description

Lumason (sulfur hexafluoride lipid-type
A microspheres) for injectable suspension, for intravenous or intravesical
use is used to prepare the ultrasound contrast agent. The single-patient
use kit contains the following three items:1) 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-cap2) one prefilled syringe containing 5 mL Sodium
Chloride 0.9% Injection, USP (Diluent)3) one Mini-SpikeEach 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, SF6, or 60.7 mg per
vial.Each prefilled
syringe with 5 mL of diluent 0.9% Sodium Chloride Injection is sterile,
nonpyrogenic, preservative free containing 9 mg sodium chloride per
mL.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 SF6 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-Distearoyl-sn-glycero-3-phosphocholine
(DSPC), with empirical formula C44H88NO8P, 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 C38H74 NaO10P, has a molecular
weight of 745 and the following chemical structure:Each milliliter of reconstituted Lumason suspension contains 1.5
to 5.6 x 108 microspheres, 68 mcg SF6 (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 CharacteristicsMean diameter range1.5 – 2.5 μmPercent of microspheres
≤ 10 µm≥ 99%Upper size limit100.0% ≤ 20 µm

12.1  Mechanism Of Action

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.

12.2  Pharmacodynamics

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
EffectsThe
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.

12.3  Pharmacokinetics

The pharmacokinetic of the SF6 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 SF6 in blood peaked
within 1 to 2 minutes for both doses. The terminal half-life of SF6 in blood was approximately 10 minutes for the 0.3 mL/kg
dose. The area-under-thecurve of SF6 was dose-proportional
over the dose range studied.DistributionIn a study of healthy subjects,
the mean values for the apparent steady-state volume of distribution
of SF6 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.EliminationFollowing intravenous administration, the SF6 component of Lumason is eliminated via the lungs. In a clinical
study that examined SF6 elimination twenty
minutes following Lumason injection, the mean cumulative recovery
of SF6 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.SF6 undergoes
first pass elimination within the pulmonary circulation; approximately
40% to 50% of the SF6 content was eliminated
in the expired air during the first minute following Lumason injection.MetabolismSF6 undergoes little or no biotransformation; following intravenous
administration, 88% of an administered dose is recovered unchanged
in expired air.Pharmacokinetics in Specific PopulationsPulmonary Impairment:In a study of patients with pulmonary
impairment, blood concentrations of SF6 peaked
at 1 to 4 minutes following Lumason administration. The cumulative
recovery of SF6 in expired air was 102 ± 18%
(mean ± standard deviation), and the terminal half-life of SF6 in blood was similar to that measured in healthy subjects.

13.1  Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

14.1  Echocardiography

AdultsA 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 EffectIn 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
DelineationReaderStudy
AN = 76Study
BN = 62Study
CN = 53Non-contrastLumasonNon-contrastLumasonNon-contrastLumasonA60 (79%)22 (33%)31 (50%)12 (19%)12 (23%)10 (19%)B62 (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 OpacificationIn 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 patientsTwelve 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 DelineationEvaluation 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 patientTable 4. Number of Pediatric Patients with Inadequate Border Delineation
with and without LumasonReader AReader BReader CNon-contrast12/1211/11b2/12Lumason1/11a0/9bb0/11cLeft Ventricular
OpacificationComplete left ventricular opacification
was observed in all the patients by all 3 readers following administration
of Lumason.

14.2  Ultrasonography Of The Liver

AdultsA 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 LesionsStudy
A:Sensitivity
(patients with malignant lesions)N=119Specificity
(patients with benign lesions)N=140Lumason%Non-contrast%Difference(95% CI)Lumason%Non-contrast%Difference(95% CI)Reader 187*4938 (30, 54)71638 (-4, 21)Reader 276*3541 (29, 52)83*5429 (21, 44)Reader 392*1676 (67, 84)73*2251 (40, 61)Study
B:Sensitivity
(patients with malignant lesions)N=124Specificity
(patients with benign lesions)N=116Lumason%Non-contrast%Difference(95% CI)Lumason%Non-contrast%Difference(95% CI)Reader 4655312 (-1, 23)72*2448 (35, 58)Reader 561*4120 (7, 32)67*760 (50, 70)Reader 64766-19 (-31, -7)88*5929 (18, 40)Pediatric patientsIn 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).

14.3  Ultrasonography Of The Urinary Tract

Pediatric PatientsThe 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.

Other

  • 16.1  How Supplied Lumason (sulfur hexafluoride lipid-type A
  • Microspheres) for injectable suspension is supplied as a single patient-
  • Use kit as follows:One Lumason vial of 25 mg lipid-type A white lyophilized
  • Powder with headspace fill of 60.7 mg of sulfur hexafluorideOne prefilled syringe containing 5mL of Sodium Chloride
  • 0.9% Injection, USP (Diluent)One Mini-SpikeEach kit is packaged in
  • A clear plastic container. (NDC 0270-7099-73) 5 Kits per
  • Carton

16.2  Storage and HandlingStore the kit at 25°C (77°F); excursions
permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

17  Patient Counseling Information

Advise patients to inform their healthcare
provider if they develop any symptoms of hypersensitivity after LUMASON
administration including rash, wheezing, or shortness of breath.Manufactured for:Bracco
Diagnostics Inc., Monroe Township, NJ 08831byBRACCO Suisse SAPlan-les-Ouates Geneve, Switzerland
(Lumason lyophilized powder vial-25 mg lipid-type A/60.7 mg sulfur
hexafluoride gas)Vetter
Pharma-Fertigung GmbH & Co. KG88212 Ravensburg, Germany
(Sodium Chloride 0.9% Injection, USP)B. Braun Melsungen AG34212 Melsungen,
Germany (Mini-Spike)This product is covered by US Patent No. 5,686,060Novaplus is a registered trademark of Vizient,
Inc.Revised November
2019CL108202

* Please review the disclaimer below.