Sulfur hexafluoride lipid-type A microspheres is an ultrasound contrast agent for echocardiography to opacify the left ventricular chamber and to delineate the left ventricular endocardial border in adult and pediatric patients with suboptimal echocardiograms and for hepatic ultrasonography to enhance characterization of focal hepatic lesions in adult and pediatric patients. It is also used for ultrasonography of the urinary tract for assessment of suspected or known vesicoureteral reflux in pediatric patients. Approval was based on the results of 4 clinical trials involving a total of 191 adults and 12 pediatric patients (9 to 17 years) with suspected cardiac disease and suboptimal non-contrast echocardiography, 3 trials involving a total of 499 adults and 44 pediatric patients (4 to 18 years) with at least 1 indeterminate focal hepatic lesion, and 2 trials involving 411 pediatric patients (2 days to 13 years) with suspected or known vesicoureteral reflux. In all echocardiography trials, sulfur hexafluoride lipid-type A microspheres improved left ventricular endocardial border delineation when compared to non-contrast images. In addition, complete left ventricular opacification was observed in 52% to 80% of adult patients and 100% of pediatric patients. In the hepatic ultrasonography trials, use of the drug significantly improved characterization of focal hepatic lesions when compared to non-contrast ultrasound images in both adult and pediatric patients. In the urinary tract voiding ultrasonography trials, sulfur hexafluoride lipid-type A microspheres was compared to the radiographic reference standard (voiding cystourethrography). Of 174 reference standard-positive images, sulfur hexafluoride lipid-type A microspheres ultrasonography was positive in 146 units and falsely negative in 28 units. In 655 units with negative reference standards, sulfur hexafluoride lipid-type A microspheres ultrasonography was negative in 528 units and falsely positive in 127 units. Prior to drug administration, ensure ready access to cardiopulmonary resuscitation equipment and trained personnel, as serious (sometimes fatal) cardiopulmonary reactions have been reported with ultrasound contrast agents, including sulfur hexafluoride lipid-type A microspheres. In addition, before injecting the contrast agent, the ultrasound mechanical index must be adjusted to 0.8 or lower for echocardiography or 0.4 or lower for hepatic or urinary tract ultrasonography. Failure to adjust the mechanical index may result in reduced efficacy and adverse events.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Hypersensitivity reactions may occur. Prior to administration, assess all patients for previous reactions to any of the active or inactive ingredients. Trained personnel and therapies used to treat hypersensitivity reactions (epinephrine, antihistamines, and corticosteroids) should be readily available. Observe patient for signs and symptoms of hypersensitivity reactions during and after administration.
NOTE: Serious cardiopulmonary reactions have occurred following administration of ultrasound contrast agents. Ensure cardiopulmonary resuscitation equipment and trained personnel are readily available prior to drug administration. Monitor all drug recipients for acute reactions.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the protective caps on vial or a prefilled syringe are not intact, or if other signs of damage are present. Once reconstituted, the suspension is milky white; discard if discolored.
-Administer immediately after reconstitution. If the drug is not used immediately after reconstitution, resuspend the microspheres for a few seconds by hand agitation before the dose is drawn into the syringe.
-Storage: Reconstituted suspension within a vial may be used for up to 3 hours from the time of reconstitution. Store the vial containing the reconstituted suspension at room temperature of 15 to 30 degrees C (59 to 86 degrees F).
Reconstitution of Single Patient Use Kit
-Do not use a single use vial for more than 1 patient.
-Connect the plunger rod to the prefilled 0.9% Sodium Chloride Injection syringe by twisting in a clockwise direction.
-Remove the syringe tip cap, open the Mini-Spike blister, and remove the Mini-Spike green cap. Connect the syringe to the Mini-Spike by twisting in a clockwise direction. Remove the vial cap and the Mini-Spike protection. Fully insert the spike into the center of the rubber vial stopper by pressing firmly.
-Push the plunger to empty the contents of the syringe into the vial. While keeping the syringe, Mini-Spike, and vial connected, shake the product vigorously for 20 seconds to produce a homogeneous white milky suspension.
-For doses 1 mL or more: Invert the system and slowly withdraw the required volume of suspension into the syringe.
-For doses less than 1 mL: Invert the system and slowly withdraw 2 mL of suspension into the 5 mL syringe. Then measure the volume to be injected by using the 0.2 mL graduations between the 1 and 2 mL markings.
-Unscrew the syringe from the Mini-Spike. Peel and remove the diluent label to display the reconstituted product label.
Reconstitution of 20-Vial Pack
-Obtain a 5 mL syringe with luer lock tip, and fill with 5 mL of additive-free 0.9% Sodium Chloride Injection to use as the diluent. A prefilled syringe containing additive-free 0.9% Sodium Chloride Injection may be used. Use 2 health care professionals to verify that the solution selected for reconstitution is additive-free 0.9% Sodium Chloride Injection. Ensure all air in the syringe is expelled.
-Remove the Mini-Spike green cap and connect the syringe to the Mini-Spike by twisting clockwise.
-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.
-Empty the entire 5 mL content of the syringe into the vial by pushing on the plunger rod. While keeping the syringe, Mini-Spike, and vial connected, shake the product vigorously for 20 seconds to produce a homogeneous white milky suspension.
-To obtain the required dose, invert the system and slowly withdraw the intended volume of suspension into the syringe.
-Unscrew the syringe from the Mini-Spike. Label the syringe using the provided peel-off sticker.
Route-Specific Administration
Injectable Administration
Intravenous Administration
-Immediately connect the syringe to a dose administration line (20 gauge).
-Administer by IV bolus.
-Follow the bolus injection with 5 mL of 0.9% Sodium Chloride Injection flush.
-A second dose may be administered if prolonged contrast enhancement is required.
-For echocardiography: After baseline non-contrast echocardiography is complete, adjust the mechanical index of the ultrasound device to 0.8 or less.
-For hepatic ultrasonography: After identification of target focal lesion on non-contrast ultrasound exam, hold transducer still while switching the scanner to low mechanical index (0.4 or less) contrast-specific imaging.
Other Administration Route(s)
Intravesical Administration
-After baseline non-contrast ultrasound examination of the kidney and bladder, switch to low mechanical index (0.4 or less) contrast-specific imaging. Perform continuous alternate ultrasound imaging of the bladder, ureters, and kidneys during filling and voiding of the bladder.
-Insert a sterile catheter (6 to 8 french) into the bladder under sterile conditions, and connect the syringe containing sulfur hexafluoride lipid-type A microspheres to the catheter.
-Empty the bladder of urine, and then fill the bladder with sterile 0.9% Sodium Chloride Injection to approximately one-third or half of its predicted volume. The total bladder volume in children is calculated as: [(age in years +2) x 30] mL.
-Administer sulfur hexafluoride lipid-type A microspheres as an intravesical bolus injection through the urinary catheter.
-Continue filling the bladder with 0.9% Sodium Chloride Injection until the patient has the urge to micturate or at the first sign of back pressure to the infusion.
-Immediately after the first voiding, the bladder may be refilled with 0.9% Sodium Chloride Injection for a second cycle of voiding and imaging, without the need for a second sulfur hexafluoride lipid-type A microspheres injection.
Serious cardiopulmonary reaction, including fatalities, have been reported during or shortly after (30 minutes) administration of ultrasound contrast agents such as sulfur hexafluoride lipid-type A microspheres. Reported reactions include fatal cardiac arrest, fatal respiratory arrest, shock, syncope, symptomatic arrhythmia exacerbation (atrial fibrillation, sinus tachycardia, bradycardia, supraventricular tachycardia (SVT), ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain (unspecified) (0.2%), respiratory distress, stridor, wheezing, loss of consciousness, and seizures.
Serious hypersensitivity or anaphylactoid reactions have been noted during or shortly after sulfur hexafluoride lipid-type A miscrospheres administration, typically within 30 minutes. These reactions include anaphylaxis, with manifestations that may include death, anaphylactic shock, bronchospasm, dyspnea, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, localized, peripheral edema), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema.
An injection site reaction (e.g., injection site pain, injection site warmth, feeling hot) was reported in 0.2% to 0.3% of patients receiving sulfur hexafluoride lipid-type A microspheres during clinical trials.
Headache (1%), nausea (0.5%), dysgeusia (0.4%), and dizziness (0.2%) were among the most frequently reported adverse reactions by sulfur hexafluoride lipid-type A microspheres recipients during clinical trials.
Sulfur hexafluoride lipid-type A microspheres is contraindicated for use in individuals with a known or suspected history of hypersensitivity to sulfur hexafluoride lipid-type A microspheres or its components, such as polyethylene glycol (PEG). Serious hypersensitivity reactions, including anaphylaxis with manifestations that may include death, have been noted during or shortly after sulfur hexafluoride lipid-type A microspheres administration. These reactions may develop in patients with no prior exposure to sulfur hexafluoride lipid-containing microspheres. There may be an increased risk of serious reactions, including death, in patients with prior hypersensitivity reactions to PEG. Assess patients for prior hypersensitivity reactions to products containing PEG, such as certain colonoscopy bowel preparations and laxatives. Ensure cardiopulmonary resuscitation personnel and equipment are readily available before sulfur hexafluoride lipid-type A microspheres administration, and monitor all patients for hypersensitivity reactions.
Serious cardiopulmonary reaction, including some fatalities, have occurred during or immediately following the administration of sulfur hexafluoride lipid-type A microspheres. These reactions (e.g., fatal cardiac or respiratory arrest, shock, syncope, cardiac arrhythmias, hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, convulsions) typically develop within 30 minutes of drug administration. Patients at increased risk include those with unstable cardiopulmonary conditions such as acute myocardial infarction, acute coronary artery disease, worsening or unstable heart failure, or serious ventricular arrhythmias. Have cardiopulmonary resuscitation personnel and equipment readily available before administration, and monitor all patients for acute reactions. Additionally, before contrast administration, the ultrasound mechanical index value must be adjusted to 0.8 or lower for echocardiography or 0.4 or lower for hepatic and urinary tract ultrasonography. Failure to adjust the mechanical index value may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Further, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias.
Use sulfur hexafluoride lipid-type A microspheres with caution in patients with arteriovenous shunt. In these patients, microspheres may bypass filtering by the lung and directly enter the arterial circulation resulting in systemic embolization. Assess patients with shunts for embolic phenomena after sulfur hexafluoride lipid-type A microspheres administration.
Avoid intraarterial administration of sulfur hexafluoride lipid-type A microspheres. The drug is only for intravenous or intravesical administration.
There are no data with sulfur hexafluoride lipid-type A microspheres in pregnancy to inform any drug-associated risks. No adverse developmental outcomes were noted in animal reproduction studies when sulfur hexafluoride lipid-type A microspheres was administered to rats and rabbits during organogenesis at doses up to 10- and 20-times the recommended human dose, respectively.
There are no data on the presence of sulfur hexafluoride lipid-type A microspheres in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for sulfur hexafluoride lipid-type A microspheres and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.
For use during ultrasound imaging (i.e., echocardiography, hepatic ultrasonography, and urinary tract ultrasonography):
-for use during echocardiography to opacify the left ventricular chamber and improve delineation of the left ventricular endocardial boarder in patients with suboptimal echocardiograms:
Intravenous dosage:
Adults: 2 mL IV bolus. A second 2 mL IV bolus may be administered if prolonged contrast enhancement is needed. Follow each sulfur hexafluoride lipid-type A microspheres injection with a 5 mL 0.9% Sodium Chloride Injection flush. The recommended 2 mL dose will enhance the echocardiographic signal for approximately 2 minutes.
Infants, Children, and Adolescents: 0.03 mL/kg IV bolus (Max: 2 mL/dose). A second 0.03 mL/kg IV bolus (Max: 2 mL/dose) may be administered if prolonged contrast enhancement is needed. Follow each sulfur hexafluoride lipid-type A microspheres injection with a 5 mL 0.9% Sodium Chloride Injection flush. The recommended dose will enhance the echocardiographic signal for approximately 2 minutes.
-for use during hepatic ultrasonography to characterize focal hepatic lesions:
Intravenous dosage:
Adults: 2.4 mL IV bolus. A second 2.4 mL IV bolus may be administered if prolonged contrast enhancement is needed. Follow each sulfur hexafluoride lipid-type A microspheres injection with a 5 mL 0.9% Sodium Chloride Injection flush.
Infants, Children, and Adolescents: 0.03 mL/kg IV bolus (Max: 2.4 mL/dose). A second 0.03 mL/kg IV bolus (Max: 2.4 mL/dose) may be administered if prolonged contrast enhancement is needed. Follow each sulfur hexafluoride lipid-type A microspheres injection with a 5 mL 0.9% Sodium Chloride Injection flush.
-for use during urinary tract ultrasonography for the evaluation of known or suspected vesicoureteral reflux:
Intravesical dosage:
Infants, Children, and Adolescents: 1 mL by intravesical injection. The bladder may be refilled with normal saline for a second cycle of voiding and imaging without the need for a second sulfur hexafluoride lipid-type A microspheres injection.
Neonates: 1 mL by intravesical injection. The bladder may be refilled with normal saline for a second cycle of voiding and imaging without the need for a second sulfur hexafluoride lipid-type A microspheres injection.
Maximum Dosage Limits:
-Adults
2 mL/dose IV for echocardiography; 2.4 mL/dose for hepatic ultrasonography. Safety and efficacy have not been established for urinary tract ultrasonography.
-Geriatric
2 mL/dose IV for echocardiography; 2.4 mL/dose for hepatic ultrasonography. Safety and efficacy have not been established for urinary tract ultrasonography.
-Adolescents
0.03 mL/kg IV for echocardiography (Max: 2 mL/dose) or hepatic ultrasonography (Max: 2.4 mL/dose); 1 mL/dose intravesically for urinary tract ultrasonography.
-Children
0.03 mL/kg IV for echocardiography (Max: 2 mL/dose) or hepatic ultrasonography (Max: 2.4 mL/dose); 1 mL/dose intravesically for urinary tract ultrasonography.
-Infants
0.03 mL/kg IV for echocardiography or hepatic ultrasonography; 1 mL/dose intravesically for urinary tract ultrasonography.
-Neonates
1 mL/dose intravesically for urinary tract ultrasonography. Safety and efficacy have not been established for echocardiography or hepatic ultrasonography.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Sulfur Hexafluoride Lipid-Type A Microspheres products.
Sulfur hexafluoride lipid-type A microspheres enhance ultrasound imaging. The microspheres exhibit lower acoustic impedance than does the surrounding non-aqueous tissue. As a result, the ultrasound beam is reflected from the interface between the microspheres and tissue, thereby providing a visual image that shows the contrast between the blood and surrounding tissues. For ultrasonography of the liver, sulfur hexafluoride lipid-type A microspheres provide 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. Intravesically administered sulfur hexafluoride lipid-type A microspheres increase signal intensity of fluids within the urethra, bladder, ureters, and renal pelvis, thus facilitating the detection of reflux of fluid from the bladder into the ureters.
Sulfur hexafluoride lipid-type A microspheres is administered via intravenous or intravesical bolus injection. Following IV administration, the drug preferentially distributes to the lungs, where it undergoes first pass elimination within the pulmonary circulation. Little or no metabolism occurs, with 88% of the administered dose recovered as unchanged drug in expired air. Approximately 40% to 50% of the dose is eliminated in expired air during the first minute following injection. The terminal half-life for a 0.3 mL/kg dose (10-times the recommended dose) is 10 minutes. Sulfur hexafluoride lipid-type A microspheres are destroyed and enhancement decreases as the mechanical index increases (values of 0.8 or less are recommended).
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Intravenous Route
Sulfur hexafluoride lipid-type A microspheres doses of 0.03 mL/kg and 0.3 mL/kg (approximately 1- and 10-times the recommended dose) were evaluated in 12 healthy adult subjects. After IV bolus administration, peak serum concentrations (Cmax) were achieved within 1 to 2 minutes (Tmax) for both doses. Exposure (AUC) was found to be dose-proportional. At the recommended dose of 2 mL, the echocardiographic signal is enhanced for approximately 2 minutes post-injection (range 1.7 to 3.1 minutes).
-Special Populations
Other
Pulmonary Impairment
The pharmacokinetics of sulfur hexafluoride lipid-type A microspheres were evaluated in a study of patients with pulmonary impairment. Patients in this study achieved maximum serum drug concentrations at 1 to 4 minutes post-injection, compared to 1 to 2 minutes for healthy subjects. The terminal half-lives were similar between the 2 groups; however, the cumulative recovery of the drug in expired air was 102 +/- 18% for those with pulmonary impairment, compared to 82 +/- 20% (0.03 mL/kg) and 88 +/- 26% (0.3 mL/kg) for healthy subjects.