Sulfur Hexafluoride

1 INDICATIONS AND USAGE Echocardiography Lumason is indicated for use in adult and pediatric patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. Ultrasonography of the Liver Lumason is indicated for use with ultrasound of the liver in adult and pediatric patients to characterize focal liver lesions. Ultrasonography of the Urinary Tract Lumason is indicated for use in ultrasonography of the urinary tract in pediatric patients for the evaluation of suspected or known vesicoureteral reflux. Lumason is an ultrasound contrast agent indicated for use in echocardiography to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border in adult and pediatric patients with suboptimal echocardiograms ( 1 ) in ultrasonography of the liver for characterization of focal liver lesions in adult and pediatric patients ( 1 ) in ultrasonography of the urinary tract for the evaluation of suspected or known vesicoureteral reflux in pediatric patients ( 1 )

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 2 mL as an intravenous injection ( 2.2 , 2.4 ) Echocardiography in pediatric patients: After reconstitution, administer 0.03 mL per kg as an intravenous injection up to a maximum of 2 mL per injection ( 2.2 , 2.4 ) Ultrasonography of the liver in adults: After reconstitution, administer 2.4 mL as an intravenous injection ( 2.2 , 2.4 ) Ultrasonography of the liver in pediatric patients: After reconstitution, administer 0.03 mL per kg as an intravenous injection, up to a maximum of 2.4 mL per injection ( 2.2 , 2.4 ) May repeat dose one time during a single examination ( 2.2 , 2.4 ) Follow each injection with an intravenous flush of 0.9% Sodium Chloride Injection, USP ( 2.2 , 2.4 ) For intravesical administration in pediatric patients : Ultrasonography of the urinary tract: After reconstitution, administer 1 mL via sterile 6 to 8F urinary catheter. Bladder should be first emptied and then partially filled with 0.9% Sodium Chloride Injection, USP before injection of Lumason ( 2.2 , 2.4 ) After Lumason administration, continue filling the bladder with 0.9% Sodium Chloride Injection, USP until the patient has the urge to micturate or at the first sign of back pressure to the infusion ( 2.4 ) 2.1 Important Administration Instructions Do not administer Lumason by intra-arterial injection [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage Echocardiography Adults The recommended dose of Lumason after reconstitution is 2 mL administered as an intravenous bolus injection during echocardiography. During a single examination, a second injection of 2 mL may be administered to prolong contrast enhancement. Follow each Lumason injection with an intravenous flush using 5 mL of 0.9% Sodium Chloride Injection, USP. Pediatric Patients The recommended dose of Lumason after reconstitution in pediatric patients is 0.03 mL per kg administered as an intravenous injection during echocardiography. During a single examination, a second injection of 0.03 mL per kg may be administered, if needed. Do not exceed 2 mL per injection. Follow Lumason injection with an intravenous flush using 5 mL of 0.9% Sodium Chloride Injection, USP. Ultrasonography of the Liver Adults The recommended dose of Lumason after reconstitution in adult patients is 2.4 mL administered as an intravenous injection during ultrasonography of the liver. During a single examination, a second injection of 2.4 mL may be administered, if needed. Follow Lumason injection with an intravenous flush using 5 mL of 0.9% Sodium Chloride Injection, USP. Pediatric Patients The recommended dose of Lumason after reconstitution in pediatric patients is 0.03 mL per kg administered as an intravenous injection during ultrasonography of the liver. During a single examination, a second injection of 0.03 mL per kg may be administered, if needed. Do not exceed 2.4 mL per injection. Follow Lumason injection with an intravenous flush of 0.9% Sodium Chloride Injection, USP. Ultrasonography of the Urinary Tract Pediatric Patients The recommended dose of Lumason after reconstitution is 1 mL. The bladder may be refilled with 0.9% Sodium Chloride Injection, USP for a second cycle of voiding and imaging, without the need of a second Lumason administration. 2.3 Reconstitution Instructions Refer to Section 2.3.1 for instructions for using the single patient use kit with diluent provided Refer to Section 2.3.2 for instructions for using the 20-vial pack without diluent provided 2.3.1 Lumason Kit (single patient use kit) Contents of Lumason Kit Inspect the Lumason kit and its components for signs of damage. Do not use the kit if the protective caps on the Lumason vial and prefilled syringe with 5 mL 0.9% Sodium Chloride Injection, USP are not intact or if the kit shows other signs of damage. Under aseptic conditions, reconstitute the Lumason vial using the following illustrated steps: 1. Connect the plunger rod to the prefilled 0.9% Sodium Chloride Injection, USP syringe barrel by screwing it clockwise into the syringe (see Figure 1). 2. Open the Mini-Spike blister and remove the syringe tip cap (see Figure 2). 3. Remove the Mini-Spike green cap and connect the syringe to the Mini-Spike by screwing it in clockwise (see Figure 3). 4. Remove the Mini-Spike spike protection and position the spike in the center of the rubber stopper of the vial. Press firmly inward until the spike is fully inserted in the stopper (see Figure 4). 5. Empty the content of the syringe into the vial by pushing on the plunger rod (see Figure 5). 6. Shake vigorously for 20 seconds, mixing all the contents in the vial (see Figure 6). A homogeneous white milky liquid indicates formation of sulfur hexafluoride lipid microspheres. 7. For preparation of doses greater than or equal to 1 mL, invert the system and slowly withdraw the intended volume of suspension into the syringe (see Figure 7). For preparation of doses less than 1 mL, withdraw 2 mL of the reconstituted suspension into the 5 mL syringe and measure the volume of Lumason to inject by using the 0.2 mL graduations between the 1 mL and 2 mL marks. 8. Unscrew the syringe from the Mini-Spike (see Figure 8). Peel and remove the diluent label to display the reconstituted product label. For intravenous administration, immediately connect the syringe to a dose administration line (20 G) and administer as directed under the Administration Instructions below. For intravesical administration, immediately connect the syringe to a sterile urinary catheter (6 French to 8 French) and administer as directed under the Administration Instructions below. Following reconstitution, Lumason suspension contains 1.5 to 5.6 x10 8 microspheres/mL with 45 mcg/mL of sulfur hexafluoride. Use immediately after reconstitution. If the suspension is not used immediately after reconstitution, resuspend the microspheres for a few seconds by hand agitation before the suspension is drawn into the syringe. Reconstituted suspension within a vial may be used for up to 3 hours from the time of its reconstitution. Maintain the vial containing the reconstituted suspension at room temperature 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). glass-vial-spike-syringe-and-rod figure 1 figure 2 figure 3 figure 4 figure 5 figure 6 figure 7 figure 8 2.3.2 Lumason Pack (20-vial pack) Contents of Lumason Pack *Please note: This presentation does not include pre-filled syringes of 0.9% Sodium Chloride Injection, USP (Diluent). Lumason vials are to be used with the supplied Mini-Spike only. Use only additive-free 0.9% Sodium Chloride Injection, USP for the reconstitution of Lumason. Reconstitution Inspect the Lumason components for signs of damage. Do not use the Lumason vial if the protective cap on the vial is not intact or other components in the pack show signs of damage. Use aseptic conditions for the preparation and administration of Lumason. 1. Obtain a 5 mL syringe, with luer lock tip, and fill with 5 mL of additive-free 0.9% Sodium Chloride Injection, USP (diluent) (see Figure 1). Two healthcare professionals (HCPs) should verify that the solution selected for reconstitution of Lumason is additive-free 0.9% Sodium Chloride Injection, USP. Ensure that any air in the syringe is expelled. [Note: A prefilled syringe containing additive-free 0.9% Sodium Chloride Injection, USP may be used. Ensure that any air in the syringe is expelled.] 2. Remove the Mini-Spike green cap and connect the syringe to the Mini-Spike by screwing it in clockwise (see Figure 2). 3. Remove the Mini-Spike spike protection and position the spike in the center of the rubber stopper of the vial. Press firmly inward until the spike is fully inserted in the stopper (see Figure 3). 4. Empty the entire 5 mL content of the syringe into the vial by pushing on the plunger rod (see Figure 4). 5. Shake vigorously for 20 seconds, mixing all the contents in the vial (see Figure 5). A homogeneous white milky liquid indicates formation of sulfur hexafluoride lipid microspheres. 6. To obtain required dose, invert the system and slowly withdraw the intended volume of suspension into the syringe (see Figure 6). 7. Unscrew the syringe from the Mini-Spike (see Figure 7). 8. Label the syringe using the peel-off sticker provided. 9. For intravenous administration, immediately connect the syringe to a dose administration line (20G) and administer as directed under the Administration Instructions below. For intravesical administration, immediately connect the syringe to a sterile urinary catheter (6 French to 8 French) and administer as directed under the Administration Instructions below. Following reconstitution, Lumason suspension contains 1.5 to 5.6 x10 8 microspheres/mL with 45 mcg/mL of sulfur hexafluoride. Use immediately after reconstitution. If the suspension is not used immediately after reconstitution, resuspend the microspheres for a few seconds by hand agitation before the suspension is drawn into the syringe. Reconstituted suspension within a vial may be used for up to 3 hours from the time of its reconstitution. Maintain the vial containing the reconstituted suspension at room temperature 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). glass vial spike labels figure figure 1 figure 2 figure 3 figure 4 figure 5 figure 6 figure 7 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 Administration Administer Lumason as an intravenous bolus injection. Intravesical Administration in Pediatric Patients Insert a sterile 6 French to 8 French urinary catheter into the bladder under sterile conditions; Empty the bladder of urine, and then fill the bladder with sterile 0.9% Sodium Chloride Injection, USP to approximately one third or half of its predicted total volume. The total bladder volume in children is calculated as [(age in years + 2) x 30] mL; Administer Lumason as an intravesical bolus injection through the urinary catheter; Continue filling the bladder with 0.9% Sodium Chloride Injection, USP until the patient has the urge to micturate or at the first sign of back pressure to the infusion. Immediately following the first voiding, the bladder may be refilled with 0.9% Sodium Chloride Injection, USP for a second cycle of voiding and imaging, without the need of a second Lumason administration. 2.5 Imaging Guidelines Echocardiography After baseline non-contrast echocardiography is complete, adjust the mechanical index for the ultrasound device to 0.8 or lower. Continue ultrasound imaging following Lumason injection. Ultrasonography of the Liver After identification of the target focal lesion on non-contrast ultrasound examination, hold transducer still while switching scanner to low mechanical index (≤ 0.4) contrast-specific imaging. Continue ultrasound imaging following Lumason injection. Ultrasonography of the Urinary Tract After baseline non-contrast ultrasound examination of the kidney and bladder, switch the scanner to low mechanical index (≤0.4) contrast specific imaging. Perform continuous alternate ultrasound imaging of the bladder, ureters, and kidneys during filling and voiding of the bladder.

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 )] 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 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. Adults In 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 patients Table 1. Adverse Reactions in Adult Patients* n = 6856 Number (%) of Patients with Adverse Reactions 340 (5%) Headache 65 (1%) Nausea 37 (0.5%) Dysgeusia 29 (0.4%) Injection site pain 23 (0.3%) Feeling Hot 18 (0.3%) Chest discomfort 17 (0.2%) Chest pain 12 (0.2%) Dizziness 11 (0.2%) Injection Site Warmth 11 (0.2%) Pediatric Patients: In 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. These serious reactions may be increased among patients with pre-existing PEG hypersensitivity and/or unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias) [see Warnings and Precautions ( 5.1 , 5.2 )] . Hypersensitivity 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.

12.3 Pharmacokinetics The pharmacokinetic of the SF 6 gas component of Lumason was evaluated in 12 healthy adult subjects. After intravenous bolus injections of 0.03 mL/kg and 0.3 mL/kg of Lumason, corresponding to approximately 1 and 10 times the recommended doses, concentrations of SF 6 in blood peaked within 1 to 2 minutes for both doses. The terminal half-life of SF 6 in blood was approximately 10 minutes for the 0.3 mL/kg dose. The area-under-the-curve of SF 6 was dose-proportional over the dose range studied. Distribution In a study of healthy subjects, the mean values for the apparent steady-state volume of distribution of SF 6 following intravenous administration, were 341 mcL and 710 mcL for Lumason doses of 0.03 mL/kg and 0.3 mL/kg, respectively. Preferential distribution to the lung is likely responsible for these values. Elimination Following intravenous administration, the SF 6 component of Lumason is eliminated via the lungs. In a clinical study that examined SF 6 elimination twenty minutes following Lumason injection, the mean cumulative recovery of SF 6 in expired air was 82 ± 20% (SD) at the 0.03 mL/kg dose and 88 ± 26% (SD) at the 0.3 mL/kg dose. SF 6 undergoes first pass elimination within the pulmonary circulation; approximately 40% to 50% of the SF 6 content was eliminated in the expired air during the first minute following Lumason injection. Metabolism SF 6 undergoes little or no biotransformation; following intravenous administration, 88% of an administered dose is recovered unchanged in expired air. Pharmacokinetics in Specific Populations Pulmonary Impairment: In a study of patients with pulmonary impairment, blood concentrations of SF 6 peaked at 1 to 4 minutes following intravenous Lumason administration. The cumulative recovery of SF 6 in expired air was 102 ± 18% (mean ± standard deviation), and the terminal half-life of SF 6 in blood was similar to that measured in healthy subjects.