ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions arediscussed elsewhere in the labeling:Cardiopulmonary reactions [see Warnings and Precautions(5.1)] Hypersensitivity reactions [see Warnings and Precautions(5.2)] Cardiopulmonary reactions [see Warnings and Precautions(5.1)] Hypersensitivity reactions [see Warnings and Precautions(5.2)] Most common adverse reactions (incidence>= 0.5%) are headache and nausea (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical TrialsExperience. Because clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of drug cannotbe directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.AdultsIn completed clinical trials, total of 6984adult subjects (128 healthy volunteers and 6856 patients) receivedLumason 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). total of 79% subjects were White; 4% wereBlack; 16% were Asian; <1% were Hispanic; and <1% were in otherracial groups or race was not reported.In the clinical trials, serious adverse reactionswere observed in subjects; one who experienced hypersensitivity-typerash and presyncope and another who experienced anaphylactic shockshortly following Lumason administration.The most commonly reported adverse reactionsamong patients (occurring among at least 0.2% of patients) are listedbelow (Table 1). Most adverse reactions were mild to moderate in intensityand resolved spontaneously.occurring in at least 0.2% of patientsTable 1. Adverse Reactions in Adult Patientsn 6856Number (%) of Patients withAdverse 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 Patients:In completed clinicaltrials for echocardiography, total of 12 pediatric patients receivedLumason at dose of 0.03 mL/kg. No adverse reactions were identifiedin pediatric patients [see Clinical Studies (14.1)].. 6.2 Postmarketing Experience. In the international postmarketingclinical experience and clinical trials, serious adverse reactionshave uncommonly been reported following administration of Lumason.Because these reactions are reported voluntarily from populationof uncertain size, it is not always possible to reliably estimatetheir frequency or establish causal relationship to drug exposure.The serious adverse reactions include fatalities, especially in apattern 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.These serious reactions may be increased among patients with pre-existingPEG hypersensitivity and/or unstable cardiopulmonary conditions (acutemyocardial infarction, acute coronary artery syndromes, worseningor unstable congestive heart failure, or serious ventricular arrhythmias) [see Warnings and Precautions (5.1, 5.2)].HypersensitivityAnaphylaxis, with manifestationsthat 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.

BOXED WARNING SECTION.

WARNING: SERIOUS CARDIOPULMONARY REACTIONS. Serious cardiopulmonary reactions, includingfatalities, have occurred uncommonly during or following the injectionof ultrasound contrast agents, including sulfur hexafluoride lipidmicrospheres [see Warnings and Precautions (5.1)]. Most serious reactions occurwithin 30 minutes of administration [see Warnings and Precautions(5.1)].Assess all patients for the presence of any conditionthat precludes administration [see Contraindications (4)].Always have resuscitation equipment and trained personnelreadily available [see Warnings and Precautions (5.1)].. Assess all patients for the presence of any conditionthat precludes administration [see Contraindications (4)].. Always have resuscitation equipment and trained personnelreadily available [see Warnings and Precautions (5.1)].. WARNING: SERIOUS CARDIOPULMONARYREACTIONSSee full prescribinginformation for complete boxed warningSerious cardiopulmonary reactions,including fatalities, have occurred uncommonly during or followingthe injection of ultrasound contrast agents, including sulfur hexafluoridelipid microspheres (5.1). Most seriousreactions occur within 30 minutes of administration (5.1).Assess all patients for the presence of any conditionthat precludes administration (4).Always have resuscitation equipment and trained personnelreadily available (5.1).. Assess all patients for the presence of any conditionthat precludes administration (4).. Always have resuscitation equipment and trained personnelreadily available (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term animal studies wereperformed to evaluate the carcinogenic potential of Lumason. No evidenceof genotoxicity was found in the following studies conducted withLumason: 1) bacterial mutagenesis (Ames) assay, 2) an in vitro humanlymphocyte chromosome aberration assay, and 3) an in vivo mouse micronucleusassay.No impairmentof fertility was observed in rats receiving Lumason at doses up to8 times the human dose based on body surface area.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Within the blood, the acoustic impedanceof Lumason microspheres is lower than that of the surrounding non-aqueoustissue. Therefore, an ultrasound beam is reflected from the interfacebetween the microspheres and the surrounding tissue. The reflectedultrasound signal provides visual image that shows contrast betweenthe blood and the surrounding tissues.For ultrasonography of the urinary tractin pediatric patients, the intravesically administered Lumason microspheresincrease signal intensity of fluids within the urethra, bladder, ureters,and renal pelvis.. 12.2 Pharmacodynamics. Lumason provides useful echocardiographicsignal intensity for two minutes after intravenous injection. Lumasonmicrospheres are destroyed and contrast enhancement decreases as themechanical index increases (values of 0.8 or less are recommended).For ultrasonography of the liver,Lumason provides dynamic patterns of differential signal intensityenhancement between focal liver lesions and liver parenchyma duringthe arterial, portal venous, and late phase of signal intensity enhancementof the microvasculature.In ultrasonography of the urinary tract, Lumason facilitates thedetection of reflux of fluid from the bladder into the ureters.Pulmonary HemodynamicEffectsTheeffect of Lumason on pulmonary hemodynamics was studied in prospective,open-label study of 36 patients scheduled for right heart catheterization,including 18 with mean pulmonary arterial pressure (MPAP) 25 mmHgand 18 with MPAP <= 25 mmHg. No clinically important pulmonary hemodynamicchanges were observed. This study did not assess the effect of Lumasonon 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 ofLumason, corresponding to approximately and 10 times the recommendeddoses, concentrations of SF6 in blood peakedwithin to minutes for both doses. The terminal half-life of SF6 in blood was approximately 10 minutes for the 0.3 mL/kgdose. The area-under-the-curve of SF6 wasdose-proportional over the dose range studied.DistributionIn study of healthy subjects,the mean values for the apparent steady-state volume of distributionof 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 responsiblefor these values.EliminationFollowing intravenous administration, the SF6 component of Lumason is eliminated via the lungs. In clinicalstudy that examined SF6 elimination twentyminutes following Lumason injection, the mean cumulative recoveryof SF6 in expired air was 82 +- 20% (SD) atthe 0.03 mL/kg dose and 88 +- 26% (SD) at the 0.3 mL/kg dose.SF6 undergoesfirst pass elimination within the pulmonary circulation; approximately40% to 50% of the SF6 content was eliminatedin the expired air during the first minute following Lumason injection.MetabolismSF6 undergoes little or no biotransformation; following intravenousadministration, 88% of an administered dose is recovered unchangedin expired air.Pharmacokinetics in Specific PopulationsPulmonary Impairment:In study of patients with pulmonaryimpairment, blood concentrations of SF6 peakedat to minutes following intravenous Lumason administration. The cumulativerecovery 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Echocardiography. AdultsA total of 191 patients withsuspected cardiac disease and suboptimal non-contrast echocardiographyreceived Lumason in three multi-center controlled clinical trials(76 patients in Study A, 62 patients in Study B, and 53 patients inStudy C). Among these patients, there were 127 men and 64 women. Themean age was 59 years (range 22 to 96 years). The racial and ethnicrepresentations were 79% White, 16% Black, 4% Hispanic, 1% Asian,and 1% other racial or ethnic groups. The mean weight was 204lbs (range 92 to 405 lbs). Approximately 20% of the patients had achronic pulmonary disorder and 30% had history of heart failure.Of the 106 patients for whom New York Heart Association (NYHA) classificationof heart failure was assigned, 49% were Class I, 33% were Class II,and 18% were Class III. Patients with NYHA Class IV heart failurewere not included in these studies.In Studies and B, each patient receivedfour intravenous bolus injections of Lumason (0.5, 1, 2, and mL),in randomized order. In Study C, each patient received two doses ofLumason (1 mL and mL) in randomized order. All three studies assessedendocardial border delineation and left ventricular opacification.For each patient in each study, echocardiography with Lumason wascompared to non-contrast (baseline) echocardiography. recordingof 2D echocardiography was obtained from 30 seconds prior to eachinjection to at least 15 minutes after dosing or until the disappearanceof the contrast effect, whichever was longer. Contrast and non-contrastechocardiographic images for each patient were evaluated by two independentreviewers, who were blinded to clinical information and the Lumasondose. Evaluation of left ventricular endocardial border consistedof segment based assessment involving six endocardial segments andusing two apical views (2- and 4-chamber views).Endocardial Border Delineationand Duration of Useful Contrast EffectIn all three studies, administration of Lumasonimproved left ventricular endocardial border delineation. The majorityof the patients who received 2.0 mL dose of Lumason had improvementin endocardial border delineation manifested as visualization of atleast two additional endocardial border segments. Table demonstratesthe improvement in endocardial border delineation following Lumasonadministration as reduction in percentage of patients with inadequateborder delineation in at least one pair of adjacent segments (combined2-chamber and 4-chamber view). The results are shown by reader.Table 3. Reduction in Percentage of Patients with Inadequate BorderDelineationReaderStudyAN 76StudyBN 62StudyCN 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 appearanceof contrast within the left ventricle the mean duration of usefulcontrast 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 2.0 mL dose of Lumason.The studies did not sufficiently assess the effect of Lumason uponmeasures of left ventricular ejection fraction and wall motion.Pediatric patients:Twelve pediatricpatients to 17 years of age with suspected cardiac disease and suboptimalnon-contrast echocardiography received Lumason in one prospectivemulticenter clinical trial. Patients received Lumason at dose of0.03 mL/kg (mean 1.83 mL). There were female, 10 white, and blackpatients.For boththe non-contrast and contrast-enhanced images, standard apical 4-,2-, and 3- chamber views with harmonic imaging were acquired. Contrastand non-contrast images for each patient were evaluated by three independentreviewers, who were blinded to clinical information.Endocardial Border DelineationEvaluation ofleft ventricular endocardial border delineation consisted of segment-basedassessment of the left ventricle divided into 17 endocardial segments.The delineation of each segments endocardial border was rated asinadequate, sufficient, or good. An exam was considered suboptimalif any of the patients apical views had or more adjacent segmentswith inadequate delineation scores.The majority of screened patients had adequatedelineation of the left ventricular endocardial border without administrationof contrast. The number of patients with inadequate left ventricularendocardial border delineation without contrast and after Lumasonare shown for the 12 patients, by reader, in Table 4.a Reader had missingsegment data with contrast echocardiography for one patient; Reader had missing segment data withnon-contrast echocardiography for one patient; bb Reader had missing segment data with contrastechocardiography for three patients; Reader had missing segment data with contrast echocardiographyfor one patientTable 4. Number of Pediatric Patients with Inadequate Border Delineationwith and without LumasonReader AReader BReader CNon-contrast12/1211/11b 12/12Lumason1/11a 0/9bb 0/11c Left VentricularOpacificationComplete left ventricular opacificationwas observed in all the patients by all readers following administrationof Lumason.. 14.2 Ultrasonographyof the Liver. AdultsA total of 499 patients with at least focal liver lesion requiringcharacterization were evaluated in two studies (259 patients in StudyA, 240 patients in Study B). Among these patients, there were 259men 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 meanweight was 80 kg (range 44 to 173 kg).In both studies, prior to Lumason administration,gray scale and Doppler (color or power imaging) ultrasound examinationsof the target lesion were performed using commercially available ultrasoundequipment and using standard techniques. Each patient received anintravenous injection of 2.4 mL of Lumason (up to injections wereallowed, 91% patients received injection). Following Lumason administration,ultrasound examination of the target lesion was carried out usingcontrast-specific imaging modes operating at MI <= 0.4. The probe waspositioned to provide optimal visualization over the target lesionand was kept in the same position for at least 180 seconds.Truth standard included: histology/surgery,contrast CT, contrast MRI, and/or month follow-up.For each study, the interpretation of imageswas conducted by three independent readers who were blinded to clinicaldata. Lesions were characterized as malignant or benign. Separateblinded readers assessed the truth standard images.Results of both studies demonstrated an improvementin characterization of focal liver lesions using Lumason ultrasoundcompared to non-contrast ultrasound images. Table summarizes theefficacy results by reader. Statistically significantimprovement from non-contrast (p<0.05 based on McNemars test)Table 5. Diagnostic Performance of Lumason Ultrasound for Characterizationof Focal Liver LesionsStudyA: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 1874938 (30, 54)71638 (-4, 21)Reader 2763541 (29, 52)835429 (21, 44)Reader 3921676 (67, 84)732251 (40, 61)StudyB: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)722448 (35, 58)Reader 5614120 (7, 32)67760 (50, 70)Reader 64766-19 (-31, -7)885929 (18, 40)Pediatric patientsIn one publishedstudy, 44 patients with an indeterminate focal liver lesion (23 males,21 females, age range: 4-18 years, median 11.5 years) were evaluatedafter intravenous bolus administration of 1.2 to 2.4 mL of Lumason.The findings of Lumason ultrasound images were compared to CT, MRIor histology. Specificity was 98% (43/44 patients).. 14.3 Ultrasonography of the Urinary Tract. Pediatric PatientsThe efficacy of Lumason for theevaluation of pediatric patients with suspected or known vesicoureteralreflux was established in two published open-label single center studies(A and B). Patients received mL of Lumason intravesically and underwentvoiding urosonography (VUS). Patients were also evaluated with voidingcystourethrography (VCUG) as the reference standard. The presenceor absence of urinary reflux with Lumason ultrasound was comparedto the radiographic reference standard.Study evaluated 183 patients (94 male, 89female; age days 44 months) with total of 366 kidney-ureterunits. The images were interpreted by one on-site reader, blindedto the reference standard. Out of 103 reference standard-positiveimages, Lumason VUS was positive in 89 units and falsely negativein 14 units. In 263 units with negative reference standard, the Lumasonultrasonography was negative in 226 and falsely positive in 37.Study evaluated 228 patients(123 male, 105 female; age days -13 years) with total of 463 kidney-ureterunits (some patients had more than units). The images were interpretedindependently by two on-site readers, blinded to the reference standard.Out of 71 reference standard positive images, Lumason ultrasonographywas positive in 57 and falsely negative in 14. In 392 units with negativereference standard, Lumason ultrasonography was negative in 302 andfalsely positive in 90.

CONTRAINDICATIONS SECTION.

4 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 microsphere or its components, such as polyethylene glycol (PEG) [see Warnings and Precautions (5.2) and Description (11)] . Hypersensitivity to sulfur hexafluoride lipid microspheresor its components, such as polyethylene glycol (PEG) (4). Hypersensitivity to sulfur hexafluoride lipid microspheresor its components, such as polyethylene glycol (PEG) (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Lumason (sulfur hexafluoride lipid-typeA microspheres) for injectable suspension, for intravenous or intravesicaluse is used to prepare the ultrasound contrast agent. Lumason is suppliedin two presentations (single patient use kit or 20-vial pack):The single patient use kit contains the following threetexts:one clear glass 10 mL vial containing 25 mg of white lyophilizedpowder lipid-type A, 60.7 mg of sulfur hexafluoride gas and cappedwith blue flip-capone prefilled syringe containing mL 0.9% Sodium ChlorideInjection, USP (Diluent)Each prefilled syringe with 5mL of diluent 0.9% Sodium Chloride Injection, USP is sterile, nonpyrogenic,and additive-free containing 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-typeA sterile white lyophilized powder with headspace filled with 60.7mg of sulfur hexafluoride gastwenty Mini-Spikestwenty peel-off syringe labels Each vial is formulatedas 25 mg sterile, pyrogen-free lyophilized powder containing 24.56mg 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 contains6.07 mg/mL (+- %) sulfur hexafluoride, SF6, or 60.7 mg per vial.Upon reconstitution with 5mL diluent, Lumason is milky white, homogeneoussuspension containing sulfur hexafluoride lipid-type microspheres.The suspension is isotonic and has pH of 4.5 to 7.5.The sulfur hexafluoride lipidmicrospheres are composed of SF6 gas in thecore surrounded by an outer shell monolayer of phospholipids consistingDSPC and DPPG-Na with palmitic acid as stabilizer.Sulfur hexafluoride has molecular weightof 145.9 and the following chemical structure:1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), with empirical formula C44H88NO8P, has 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 molecularweight of 745 and the following chemical structure:Each milliliter of reconstituted Lumason suspension contains 1.5to 5.6 x108 microspheres, 68 mcg SF6 (12 mcL), 0.038 mg DSPC, 0.038 mg DPPG-Na, 4.91 mgpolyethylene glycol 4000 and 0.008 mg palmitic acid. The sulphur hexafluorideassociated with the microspheres suspension is 45 mcg/mL. Fifteento twenty three percent of the total lipids in the suspension areassociated with the microspheres.The sulfur hexafluoride lipid microspherecharacteristics are listed in Table 2:Table 2. Microsphere CharacteristicsMean diameter range1.5 2.5 umPercent of microspheres<= 10 um>= 99%Upper size limit100.0% <= 20 um. The single patient use kit contains the following threetexts:one clear glass 10 mL vial containing 25 mg of white lyophilizedpowder lipid-type A, 60.7 mg of sulfur hexafluoride gas and cappedwith blue flip-capone prefilled syringe containing mL 0.9% Sodium ChlorideInjection, USP (Diluent)Each prefilled syringe with 5mL of diluent 0.9% Sodium Chloride Injection, USP is sterile, nonpyrogenic,and additive-free containing mg sodium chloride per mL.one Mini-Spike one clear glass 10 mL vial containing 25 mg of white lyophilizedpowder lipid-type A, 60.7 mg of sulfur hexafluoride gas and cappedwith blue flip-cap. one prefilled syringe containing mL 0.9% Sodium ChlorideInjection, USP (Diluent)Each prefilled syringe with 5mL of diluent 0.9% Sodium Chloride Injection, USP is sterile, nonpyrogenic,and additive-free containing 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-typeA sterile white lyophilized powder with headspace filled with 60.7mg of sulfur hexafluoride gastwenty Mini-Spikestwenty peel-off syringe labels twenty Lumason clear vials, each containing 25 mg of lipid-typeA sterile white lyophilized powder with headspace filled with 60.7mg of sulfur hexafluoride gas. twenty Mini-Spikes. twenty peel-off syringe labels. sulfur-hexafluoride-chemical-structure. empirical-formula-790-6. empirical-formula-745.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION 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 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 maximum of 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 maximum of 2.4 mL per injection (2.2, 2.4)May repeat dose one time during 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 mL via sterile 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). Echocardiography in adults: After reconstitution, administer 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 maximum of 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 maximum of 2.4 mL per injection (2.2, 2.4). May repeat dose one time during single examination (2.2, 2.4). Follow each injection with an intravenous flush of 0.9% Sodium Chloride Injection, USP (2.2, 2.4). Ultrasonography of the urinary tract: After reconstitution, administer mL via sterile 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). 2.1 Important AdministrationInstructions. Do not administer Lumason by intra-arterial injection [seeWarnings and Precautions (5.3)].. 2.2 Recommended Dosage. EchocardiographyAdultsThe recommended doseof Lumason after reconstitution is mL administered as an intravenousbolus injection during echocardiography. During single examination,a second injection of mL may be administered to prolong contrastenhancement. Follow each Lumason injection with an intravenous flushusing mL of 0.9% Sodium Chloride Injection, USP.Pediatric PatientsThe recommended dose of Lumasonafter reconstitution in pediatric patients is 0.03 mL per kg administeredas an intravenous injection during echocardiography. During singleexamination, second injection of 0.03 mL per kg may be administered,if needed. Do not exceed mL per injection. Follow Lumason injectionwith an intravenous flush using mL of 0.9% Sodium Chloride Injection,USP.Ultrasonographyof the LiverAdultsThe recommended dose of Lumason after reconstitution in adult patientsis 2.4 mL administered as an intravenous injection during ultrasonographyof the liver. During single examination, second injection of2.4 mL may be administered, if needed. Follow Lumason injection withan intravenous flush using mL of 0.9% Sodium Chloride Injection,USP.PediatricPatientsTherecommended dose of Lumason after reconstitution in pediatric patientsis 0.03 mL per kg administered as an intravenous injection duringultrasonography of the liver. During single examination, secondinjection of 0.03 mL per kg may be administered, if needed. Do notexceed 2.4 mL per injection. Follow Lumason injection with an intravenousflush of 0.9% Sodium Chloride Injection, USP.Ultrasonography of the UrinaryTractPediatric PatientsThe recommended dose of Lumason afterreconstitution is mL. The bladder may be refilled with 0.9% SodiumChloride Injection, USP for second cycle of voiding and imaging,without the need of second Lumason administration.. 2.3 ReconstitutionInstructions. Refer to Section 2.3.1 for instructions for using the singlepatient use kit with diluent providedRefer to Section 2.3.2 for instructions for using the 20-vialpack without diluent provided. Refer to Section 2.3.1 for instructions for using the singlepatient use kit with diluent provided. Refer to Section 2.3.2 for instructions for using the 20-vialpack without diluent provided. 2.3.1 Lumason Kit (singlepatient use kit). Contents of Lumason KitInspect the Lumason kit and its components for signs ofdamage. Do not use the kit if the protective caps on the Lumasonvial and prefilled syringe with 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 vialusing the following illustrated steps:1. Connect the plunger rodto the prefilled 0.9% Sodium Chloride Injection, USP syringe barrelby screwing it clockwise into the syringe (see Figure 1).2. Open the Mini-Spike blister and remove the syringe tip cap (seeFigure 2).3. Remove the Mini-Spike green cap and connectthe syringe to the Mini-Spike by screwing it in clockwise (see Figure3).4. Remove the Mini-Spike spike protection and position the spikein the center of the rubber stopper of the vial. Press firmly inwarduntil the spike is fully inserted in the stopper (see Figure 4).5. Empty the content of the syringe into the vial by pushing on theplunger rod (see Figure 5).6. Shake vigorously for 20 seconds, mixingall the contents in the vial (see Figure 6). homogeneous white milkyliquid indicates formation of sulfur hexafluoride lipid microspheres.7. For preparation of doses greater than or equal to mL, invertthe system and slowly withdraw the intended volume of suspension intothe syringe (see Figure 7). For preparation of doses less than mL,withdraw mL of the reconstituted suspension into the mL syringeand measure the volume of Lumason to inject by using the 0.2 mL graduationsbetween the mL and mL marks.8. Unscrew the syringe from the Mini-Spike (see Figure 8). Peel andremove the diluent label to display the reconstituted product label.For intravenous administration, immediately connect the syringe toa dose administration line (20 G) and administer as directed underthe Administration Instructions below. For intravesical administration,immediately connect the syringe to sterile urinary catheter (6 Frenchto French) and administer as directed under the Administration Instructionsbelow.Following reconstitution, Lumason suspension contains 1.5to 5.6 x108 microspheres/mL with 45 mcg/mLof sulfur hexafluoride.Use immediately after reconstitution. If the suspensionis not used immediately after reconstitution, resuspend the microspheresfor few seconds by hand agitation before the suspension is drawninto the syringe. Reconstituted suspension within vial may be usedfor up to hours from the time of its reconstitution. Maintain thevial containing the reconstituted suspension at room temperature 25C(77F); excursions permitted to 15 to 30C (59 to 86F).. Inspect the Lumason kit and its components for signs ofdamage. Do not use the kit if the protective caps on the Lumasonvial and prefilled syringe with 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 vialusing the following illustrated steps:. Following reconstitution, Lumason suspension contains 1.5to 5.6 x108 microspheres/mL with 45 mcg/mLof sulfur hexafluoride.. Use immediately after reconstitution. If the suspensionis not used immediately after reconstitution, resuspend the microspheresfor few seconds by hand agitation before the suspension is drawninto the syringe. Reconstituted suspension within vial may be usedfor up to hours from the time of its reconstitution. Maintain thevial containing the reconstituted suspension at room temperature 25C(77F); excursions permitted to 15 to 30C (59 to 86F).. glass-vial-spike-syringe-and-rod. figure 1. figure 2. figure 3. figure 4. figure 5. figure 6. figure 7. figure 8. 2.3.2 LumasonPack (20-vial pack). Contents of Lumason PackPlease note: This presentationdoes not include pre-filled syringes of 0.9% Sodium Chloride Injection,USP (Diluent).Lumasonvials are to be used with the supplied Mini-Spike only.Use only additive-free0.9% Sodium Chloride Injection, USP for the reconstitution of Lumason.ReconstitutionInspect the Lumason components for signs of damage. Do notuse the Lumason vial if the protective cap on the vial is not intactor other components in the pack show signs of damage.Use aseptic conditions for the preparation and administrationof Lumason.1. Obtain 5 mL syringe,with luer lock tip, and fill with mL of additive-free 0.9% SodiumChloride Injection, USP (diluent) (see Figure 1).Two healthcare professionals (HCPs) should verify that thesolution selected for reconstitution of Lumason is additive-free 0.9%Sodium Chloride Injection, USP.Ensure that any air in the syringe is expelled. [Note: prefilled syringe containing additive-free 0.9% Sodium ChlorideInjection, USP may be used. Ensure that any air in the syringe isexpelled.]2. Removethe Mini-Spike green cap and connect the syringe to the Mini-Spikeby screwing it in clockwise (see Figure 2).3. Remove the Mini-Spike spike protection and position the spikein the center of the rubber stopper of the vial. Press firmly inwarduntil the spike is fully inserted in the stopper (see Figure 3).4. Empty the entire mL content of the syringe into the vial bypushing on the plunger rod (see Figure 4).5. Shake vigorously for 20 seconds, mixing all the contents in thevial (see Figure 5). homogeneous white milky liquid indicates formationof sulfur hexafluoride lipid microspheres.6. To obtain required dose, invert the system and slowly withdrawthe 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 dose administration line (20G)and administer as directed under the Administration Instructions below. For intravesical administration, immediately connect the syringeto sterile urinary catheter (6 French to French) and administeras directed under the Administration Instructions below.Following reconstitution, Lumason suspension contains 1.5to 5.6 x108 microspheres/mL with 45 mcg/mLof sulfur hexafluoride.Use immediately after reconstitution. If the suspensionis not used immediately after reconstitution, resuspend the microspheresfor few seconds by hand agitation before the suspension is drawninto the syringe. Reconstituted suspension within vial maybe used for up to hours from the time of its reconstitution. Maintainthe vial containing the reconstituted suspension at room temperature25C (77F); excursions permitted to 15 to 30C (59 to 86F).. Inspect the Lumason components for signs of damage. Do notuse the Lumason vial if the protective cap on the vial is not intactor other components in the pack show signs of damage.. Use aseptic conditions for the preparation and administrationof Lumason.. Two healthcare professionals (HCPs) should verify that thesolution selected for reconstitution of Lumason is additive-free 0.9%Sodium Chloride Injection, USP.Ensure that any air in the syringe is expelled. Ensure that any air in the syringe is expelled.. Following reconstitution, Lumason suspension contains 1.5to 5.6 x108 microspheres/mL with 45 mcg/mLof sulfur hexafluoride.. Use immediately after reconstitution. If the suspensionis not used immediately after reconstitution, resuspend the microspheresfor few seconds by hand agitation before the suspension is drawninto the syringe. Reconstituted suspension within vial maybe used for up to hours from the time of its reconstitution. Maintainthe vial containing the reconstituted suspension at room temperature25C (77F); excursions permitted to 15 to 30C (59 to 86F).. glass vial spike labels figure. figure 1. figure 2. figure 3. figure 4. figure 5. figure 6. figure 7. 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 sterile French to 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) 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 second cycle of voiding and imaging, without the need of second Lumason administration.. Insert sterile French to 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) 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 second cycle of voiding and imaging, without the need of second Lumason administration.. 2.5 Imaging Guidelines. EchocardiographyAfter baseline non-contrastechocardiography is complete, adjust the mechanical index for theultrasound device to 0.8 or lower. Continue ultrasound imaging followingLumason injection.Ultrasonography of the LiverAfter identification of the target focallesion on non-contrast ultrasound examination, hold transducer stillwhile switching scanner to low mechanical index (<= 0.4) contrast-specificimaging. Continue ultrasound imaging following Lumason injection.Ultrasonography ofthe Urinary TractAfter baseline non-contrast ultrasound examinationof the kidney and bladder, switch the scanner to low mechanical index(<=0.4) contrast specific imaging. Perform continuous alternate ultrasoundimaging of the bladder, ureters, and kidneys during filling and voidingof the bladder.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injectable suspension: Lumasonis supplied in two presentations (single patient use kit or 20-vialpack):3-part singlepatient use kit comprised of:one Lumason clear vial containing 25 mg of lipid-type Asterile white lyophilized powder with headspace filled with 60.7 mgof sulfur hexafluoride gasone prefilled syringe containing mL of 0.9% Sodium ChlorideInjection, USP (Diluent)one Mini-Spike20-vial pack comprisedof:twenty Lumason clear vials, each containing 25 mg of lipid-typeA sterile white lyophilized powder with headspace filled with 60.7mg of sulfur hexafluoride gastwenty Mini-Spikestwenty peel-off syringe labelsFollowing reconstitution,Lumason is homogeneous, milky white suspension containing 1.5 to5.6 108 microspheres/mL with 45 mcg/mLof sulfur hexafluoride.. one Lumason clear vial containing 25 mg of lipid-type Asterile white lyophilized powder with headspace filled with 60.7 mgof sulfur hexafluoride gas. one prefilled syringe containing mL of 0.9% Sodium ChlorideInjection, USP (Diluent). one Mini-Spike. twenty Lumason clear vials, each containing 25 mg of lipid-typeA sterile white lyophilized powder with headspace filled with 60.7mg of sulfur hexafluoride gas. twenty Mini-Spikes. twenty peel-off syringe labels. For injectable suspension: 25 mg of lipid-type lyophilizedpowder with headspace fill of 60.7 mg sulfur hexafluoride in single-patientuse vial for reconstitution (3). For injectable suspension: 25 mg of lipid-type lyophilizedpowder with headspace fill of 60.7 mg sulfur hexafluoride in single-patientuse vial for reconstitution (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of 6856 adult patientsin clinical studies of Lumason, 39% were 65 and over, while 11% were75 and older. No overall differences in safety or effectiveness wereobserved between these subjects and younger subjects, and other reportedclinical experience has not identified differences in responses betweenthe elderly or younger patients, but greater sensitivity of some olderindividuals cannot be ruled out.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGEAND HANDLING. 16.1 How Supplied. Lumason (sulfur hexafluoride lipid-type microspheres) for injectable suspension is supplied as single patient use kit and as 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 white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluorideOne prefilled syringe containing 5mL of 0.9% Sodium Chloride Injection, USP (Diluent)One Mini-SpikeEach kit is packaged in clear plastic container.20-vial pack (NDC 0270-7097-08) containing:Twenty (20) Lumason vials of 25 mg lipid-type white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluorideTwenty (20) Mini-SpikesTwenty (20) peel-off syringe labels. single patient use kits (NDC 0270-7099-73) with each kit containing:One Lumason vial of 25 mg lipid-type white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluorideOne prefilled syringe containing 5mL of 0.9% Sodium Chloride Injection, USP (Diluent)One Mini-SpikeEach kit is packaged in clear plastic container.. One Lumason vial of 25 mg lipid-type 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. 20-vial pack (NDC 0270-7097-08) containing:Twenty (20) Lumason vials of 25 mg lipid-type white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluorideTwenty (20) Mini-SpikesTwenty (20) peel-off syringe labels. Twenty (20) Lumason vials of 25 mg lipid-type white lyophilized powder with headspace fill of 60.7 mg of sulfur hexafluoride. Twenty (20) Mini-Spikes. Twenty (20) peel-off syringe labels. 16.2 Storage and Handling. Store the kit at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. EchocardiographyLumason is indicatedfor use in adult and pediatric patients with suboptimal echocardiogramsto opacify the left ventricular chamber and to improve the delineationof the left ventricular endocardial border.Ultrasonography of the LiverLumason is indicatedfor use with ultrasound of the liver in adult and pediatric patientsto characterize focal liver lesions.Ultrasonography of the UrinaryTractLumasonis indicated for use in ultrasonography of the urinary tract in pediatricpatients for the evaluation of suspected or known vesicoureteral reflux.. Lumason is an ultrasound contrastagent indicated for usein echocardiography to opacify the left ventricular chamberand to improve the delineation of the left ventricular endocardialborder in adult and pediatric patients with suboptimal echocardiograms(1)in ultrasonography of the liver for characterization offocal liver lesions in adult and pediatric patients (1)in ultrasonography of the urinary tract for the evaluationof suspected or known vesicoureteral reflux in pediatric patients(1). in echocardiography to opacify the left ventricular chamberand to improve the delineation of the left ventricular endocardialborder in adult and pediatric patients with suboptimal echocardiograms(1). in ultrasonography of the liver for characterization offocal liver lesions in adult and pediatric patients (1). in ultrasonography of the urinary tract for the evaluationof suspected or known vesicoureteral reflux in pediatric patients(1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to inform their healthcareprovider if they develop any symptoms of hypersensitivity after LUMASONadministration including rash, wheezing, or shortness of breath.Manufactured for:BraccoDiagnostics Inc.Monroe Twp., NJ 08831byBRACCO Suisse SAPlan-les-Ouates Geneve, Switzerland(Lumason lyophilized powder vial-25 mg lipid- type A/60.7 mg sulfurhexafluoride gas)VetterPharma-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 registered trademark of Vizient,Inc.CL108206Revised: August 2021. novaplus logo.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Within the blood, the acoustic impedanceof Lumason microspheres is lower than that of the surrounding non-aqueoustissue. Therefore, an ultrasound beam is reflected from the interfacebetween the microspheres and the surrounding tissue. The reflectedultrasound signal provides visual image that shows contrast betweenthe blood and the surrounding tissues.For ultrasonography of the urinary tractin pediatric patients, the intravesically administered Lumason microspheresincrease signal intensity of fluids within the urethra, bladder, ureters,and renal pelvis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term animal studies wereperformed to evaluate the carcinogenic potential of Lumason. No evidenceof genotoxicity was found in the following studies conducted withLumason: 1) bacterial mutagenesis (Ames) assay, 2) an in vitro humanlymphocyte chromosome aberration assay, and 3) an in vivo mouse micronucleusassay.No impairmentof fertility was observed in rats receiving Lumason at doses up to8 times the human dose based on body surface area.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Lumason KIT Box LabelNDC: 0270-7099-73. lumason-box-label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. EchocardiographySafety and effectivenesshave been established for use in pediatric patients with suboptimalechocardiograms to opacify the left ventricular chamber and to improvedelineation of the left endocardial border. Safety and effectivenessin pediatric patients are based on adequate and well-controlled studiesin adults and are supported by clinical study in 12 pediatric patients(mean age: 13.8 years) with extrapolation of efficacy to younger pediatricpatients. No new adverse reactions were reported in the pediatricstudy [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Safety of intravenous use of Lumason was based on evaluation ofpublished literature involving the use of Lumason in over 1400 pediatricpatients (0 to 17 years).Ultrasonography of the LiverSafety and effectiveness in pediatric patientshas been established for use in ultrasonography of the liver for characterizationof focal liver lesions from adequate and well controlled trials inadult patients and clinical study of 44 pediatric patients [see Clinical Studies (14)]. Safety of intravenous use of Lumason was based on evaluation ofpublished literature involving use of Lumason in over 1400 pediatricpatients. Non-fatal anaphylaxis was reported in one pediatric patient.Ultrasonography ofthe Urinary TractSafety and effectiveness in pediatric patientshas been established for use in ultrasonography of the urinary tractfor the evaluation of suspected or known vesicoureteral reflux fromtwo published studies comprising total of 411 pediatric patients [see Clinical Studies (14)]. Safety of intravesical use of Lumason was based on evaluation ofpublished literature involving use of Lumason in over 6000 pediatricpatients. No adverse reactions were reported.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Lumason provides useful echocardiographicsignal intensity for two minutes after intravenous injection. Lumasonmicrospheres are destroyed and contrast enhancement decreases as themechanical index increases (values of 0.8 or less are recommended).For ultrasonography of the liver,Lumason provides dynamic patterns of differential signal intensityenhancement between focal liver lesions and liver parenchyma duringthe arterial, portal venous, and late phase of signal intensity enhancementof the microvasculature.In ultrasonography of the urinary tract, Lumason facilitates thedetection of reflux of fluid from the bladder into the ureters.Pulmonary HemodynamicEffectsTheeffect of Lumason on pulmonary hemodynamics was studied in prospective,open-label study of 36 patients scheduled for right heart catheterization,including 18 with mean pulmonary arterial pressure (MPAP) 25 mmHgand 18 with MPAP <= 25 mmHg. No clinically important pulmonary hemodynamicchanges were observed. This study did not assess the effect of Lumasonon visualization of cardiac or pulmonary structures.

PHARMACOKINETICS SECTION.

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 ofLumason, corresponding to approximately and 10 times the recommendeddoses, concentrations of SF6 in blood peakedwithin to minutes for both doses. The terminal half-life of SF6 in blood was approximately 10 minutes for the 0.3 mL/kgdose. The area-under-the-curve of SF6 wasdose-proportional over the dose range studied.DistributionIn study of healthy subjects,the mean values for the apparent steady-state volume of distributionof 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 responsiblefor these values.EliminationFollowing intravenous administration, the SF6 component of Lumason is eliminated via the lungs. In clinicalstudy that examined SF6 elimination twentyminutes following Lumason injection, the mean cumulative recoveryof SF6 in expired air was 82 +- 20% (SD) atthe 0.03 mL/kg dose and 88 +- 26% (SD) at the 0.3 mL/kg dose.SF6 undergoesfirst pass elimination within the pulmonary circulation; approximately40% to 50% of the SF6 content was eliminatedin the expired air during the first minute following Lumason injection.MetabolismSF6 undergoes little or no biotransformation; following intravenousadministration, 88% of an administered dose is recovered unchangedin expired air.Pharmacokinetics in Specific PopulationsPulmonary Impairment:In study of patients with pulmonaryimpairment, blood concentrations of SF6 peakedat to minutes following intravenous Lumason administration. The cumulativerecovery 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no data with Lumason use in pregnantwomen to inform any drug-associated risks. No adverse developmentaloutcomes were observed in animal reproduction studies with administrationof sulfur hexafluoride lipid-type microspheres in pregnant ratsand rabbits during organogenesis at doses up to at least 10 and 20times, respectively, the maximum human dose of 4.8 mL based on bodysurface area (see Data ).In the U.S. general population,the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataLumason was administered intravenouslyto rats at doses of 0.2, 1, and mL/kg (approximately 0.4, 2, and10 times the recommended maximum human dose of 4.8 mL, respectively,based on body surface area); Lumason doses were administered dailyfor about 30 consecutive days, from two weeks before pairing untilthe end of organogenesis. Lumason was administered intravenously torabbits at doses of 0.2, 1, and mL/kg (approximately 0.8, 4, and20 times the recommended maximum human dose, respectively, based onbody surface area); Lumason doses were administered daily from gestationday to day 19 inclusive. No significant findings on the fetus wereobserved.

RECENT MAJOR CHANGES SECTION.

Contraindications (4)4/2021Warnings and Precautions, Hypersensitivity Reactions (5.2)4/2021.

SPL UNCLASSIFIED SECTION.

2.1 Important AdministrationInstructions. Do not administer Lumason by intra-arterial injection [seeWarnings and Precautions (5.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no data with Lumason use in pregnantwomen to inform any drug-associated risks. No adverse developmentaloutcomes were observed in animal reproduction studies with administrationof sulfur hexafluoride lipid-type microspheres in pregnant ratsand rabbits during organogenesis at doses up to at least 10 and 20times, respectively, the maximum human dose of 4.8 mL based on bodysurface area (see Data ).In the U.S. general population,the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataLumason was administered intravenouslyto rats at doses of 0.2, 1, and mL/kg (approximately 0.4, 2, and10 times the recommended maximum human dose of 4.8 mL, respectively,based on body surface area); Lumason doses were administered dailyfor about 30 consecutive days, from two weeks before pairing untilthe end of organogenesis. Lumason was administered intravenously torabbits at doses of 0.2, 1, and mL/kg (approximately 0.8, 4, and20 times the recommended maximum human dose, respectively, based onbody surface area); Lumason doses were administered daily from gestationday to day 19 inclusive. No significant findings on the fetus wereobserved.. 8.2 Lactation. Risk SummaryThere are no dataon the presence of Lumason in human milk, the effects on the breastfedinfant, or the effects on milk production. The developmental and healthbenefits of breastfeeding should be considered along with the mothersclinical need for Lumason and any potential adverse effects on thebreastfed infant from Lumason or from the underlying maternal condition.. 8.4 Pediatric Use. EchocardiographySafety and effectivenesshave been established for use in pediatric patients with suboptimalechocardiograms to opacify the left ventricular chamber and to improvedelineation of the left endocardial border. Safety and effectivenessin pediatric patients are based on adequate and well-controlled studiesin adults and are supported by clinical study in 12 pediatric patients(mean age: 13.8 years) with extrapolation of efficacy to younger pediatricpatients. No new adverse reactions were reported in the pediatricstudy [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Safety of intravenous use of Lumason was based on evaluation ofpublished literature involving the use of Lumason in over 1400 pediatricpatients (0 to 17 years).Ultrasonography of the LiverSafety and effectiveness in pediatric patientshas been established for use in ultrasonography of the liver for characterizationof focal liver lesions from adequate and well controlled trials inadult patients and clinical study of 44 pediatric patients [see Clinical Studies (14)]. Safety of intravenous use of Lumason was based on evaluation ofpublished literature involving use of Lumason in over 1400 pediatricpatients. Non-fatal anaphylaxis was reported in one pediatric patient.Ultrasonography ofthe Urinary TractSafety and effectiveness in pediatric patientshas been established for use in ultrasonography of the urinary tractfor the evaluation of suspected or known vesicoureteral reflux fromtwo published studies comprising total of 411 pediatric patients [see Clinical Studies (14)]. Safety of intravesical use of Lumason was based on evaluation ofpublished literature involving use of Lumason in over 6000 pediatricpatients. No adverse reactions were reported.. 8.5 Geriatric Use. Of the total number of 6856 adult patientsin clinical studies of Lumason, 39% were 65 and over, while 11% were75 and older. No overall differences in safety or effectiveness wereobserved between these subjects and younger subjects, and other reportedclinical experience has not identified differences in responses betweenthe elderly or younger patients, but greater sensitivity of some olderindividuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cardiopulmonary reactions, including fatalities. Alwayshave resuscitation equipment and trained personnel readily available(5.1)Hypersensitivity reactions. Serious acute hypersensitivityreactions have occurred in patients with no prior exposure to sulfurhexafluoride lipid-containing microsphere products, including patientswith prior hypersensitivity reaction(s) to PEG (5.2, 6). Cardiopulmonary reactions, including fatalities. Alwayshave resuscitation equipment and trained personnel readily available(5.1). Hypersensitivity reactions. Serious acute hypersensitivityreactions have occurred in patients with no prior exposure to sulfurhexafluoride lipid-containing microsphere products, including patientswith prior hypersensitivity reaction(s) to PEG (5.2, 6). 5.1 Serious CardiopulmonaryReactions. Serious cardiopulmonary reactions, including fatalities have occurreduncommonly during or shortly following administration of ultrasoundcontrast agents, including Lumason. These reactions typically occurredwithin 30 minutes of administration. The risk for these reactionsmay be increased among patients with unstable cardiopulmonary conditions(acute myocardial infarction, acute coronary artery syndromes, worseningor unstable congestive heart failure, or serious ventricular arrhythmias). Always have cardiopulmonary resuscitation personnel and equipmentreadily available prior to Lumason administration and monitor allpatients for acute reactions.The reported reactions that may follow theadministration of ultrasound contrast agents include: fatal cardiacor respiratory arrest, shock, syncope, symptomatic arrhythmias (atrialfibrillation, 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. 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. 5.3 Systemic Embolization. When administering Lumason topatients with cardiac shunt, microspheres can bypass filtering bythe lung and enter the arterial circulation. Assess patients withshunts for embolic phenomena following Lumason administration. Lumasonis only for intravenous and/or intravesical administration; do notadminister Lumason by intra-arterial injection [see Dosageand Administration (2.1)]. 5.4 Ventricular Arrhythmia Related to High Mechanical Index. High ultrasound mechanical indexvalues may cause microsphere cavitation or rupture and lead to ventriculararrhythmias. Additionally, end-systolic triggering with high mechanicalindices has been reported to cause ventricular arrhythmias.Lumason is not recommended foruse at mechanical indices greater than 0.8.