sulfur hexafluoride (Rx)

<1%

Headache (0.9%)

Nausea (0.6%)

Dysgeusia (0.3%)

Injection site pain (0.3%)

Chest discomfort (0.3%)

Feeling hot (0.3%)

Chest pain (0.2%)

Injection site warmth (0.2%)

Postmarketing Reports

Serious reactions (typically within 30 minutes of administration) have been reported and include fatalities (symptoms suggestive of anaphylactoid/hypersensitivity), arrhythmias, and hypertensive episodes

Risk for serious cardiopulmonary reactions may increase with unstable cardiopulmonary conditions (acute MI, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias)

Contraindications

Hypersensitivity to product or components, including polyethylene glycol (PEG)

Cautions

For intravenous or intravesicular use only; do not administer by intra-arterial injection

Serious cardiopulmonary reactions, including fatalities, reported (see Black Box Warnings)

Rare anaphylactoid reactions (eg, skin erythema, rash, urticaria, flushing, throat tightness, dyspnea, anaphylactic shock) observed; may occur in patients with no history of prior exposure (see Contraindications)

Risk of systemic embolization; in patients with right-to-left, bidirectional, or transient right-to-left cardiac shunts, some IV sulfur hexafluoride lipid-containing microspheres may bypass filtering by the lung and directly enter the arterial circulation; occlusion of microcirculation by these microspheres may result in tissue ischemia; assess for embolic phenomena following administration

High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias; end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias

Hypersensitivity reactions

• In postmarketing use, serious hypersensitivity reactions were observed during or shortly following sulfur hexafluoride lipid-containing microsphere administration
• The reactions may include 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
• Product contains PEG; there may be increased risk of serious reactions including death in patients with prior hypersensitivity reaction(s) to PEG
• 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 product administration and monitor all patients for hypersensitivity reactions

Pregnancy

There are no data on use in pregnant women to inform any drug- associated risks; no adverse developmental outcomes were observed in animal reproduction studies with administration of sulfur hexafluoride lipid-type A microspheres in pregnant rats and rabbits during organogenesis at doses up to at least 10 and 20 times, respectively, the maximum human dose of 4.8 mL based on body surface area

Lactation

There are no data on presence in human milk, effects on breastfed infant, or effects on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Within the blood, acoustic impedance of the sulfur hexafluoride microspheres is lower than that of the surrounding nonaqueous tissue

This allows reflection of an ultrasound beam from the interface between the microspheres and the surrounding tissue, thus enabling a visual image between the blood and the surrounding tissues

Absorption

Peak blood concentration: 1-2 minutes

Distribution

Vd: 341 L (mostly within lung)

Metabolism

Undergoes little or no biotransformation; 88% recovered unchanged in expired air

Elimination

Half-life, terminal: 10 minutes

82% eliminated via the lungs within 20 minutes

Undergoes first pass elimination within the pulmonary circulation; ~40-50% eliminated in the expired air during the first minute following injection

IV Preparation

Using aseptic techniques, reconstitute vial using mini-spike with prefilled syringe contents (ie, 5 mL NaCl 0.9%)

Do not remove syringe and mini-spike from vial

Shake vigorously for 20 seconds, mixing all contents in the vial

Resulting suspension should appear as a homogenous, white, milky liquid; this indicates formation of sulfur hexafluoride lipid microspheres

Following reconstitution, resulting suspension contains 1.5-5.6 x10⁸ lipid microspheres/mL with 45 mcg/mL of sulfur hexafluoride

Invert vial and syringe and slowly withdraw 2 mL of the reconstituted suspension into the syringe

Unscrew syringe from mini-spike and immediately connect the syringe to the dosage administration line (20 G)

Kit contains

• 2-compartment vial containing 25 mg of lipid-type A lyophilized powder and headspace fill of 60.7 mg sulfur hexafluoride
• Prefilled syringe containing 5 mL NaCl 0.9%
• Mini-spike

IV Administration

Administer suspension as IV bolus injection immediately after reconstitution

Provides useful echocardiographic signal intensity for 2 minutes following the injection

If not used immediately after reconstitution, the microspheres should be resuspended by a few seconds of hand agitation before the suspension is withdrawn into the syringe

Intravesical (Urinary Instillation) Preparation

Doses ≥1 mL: Invert the system and slowly withdraw the intended volume of suspension into the syringe

Doses <1 mL: Withdraw 2 mL of the reconstituted suspension into the 5 mL syringe and measure the volume of sulfur hexafluoride to inject by using the 0.2 mL graduations between the 1-2 mL marks

Intravesical (Urinary Instillation) Administration

Insert a sterile 6-8 french urinary catheter into the bladder under sterile conditions

Empty the bladder of urine, and then fill the bladder with 0.9% NaCl to ~33-50% of its predicted total volume

The total bladder volume in children is calculated as: [(age in years + 2) x 30] mL

Administer as an intravesical bolus injection through the urinary catheter

Continue filling the bladder with saline until the patient has the urge to micturate or at the first sign of back pressure to the infusion

Immediately following the first voiding, the bladder may be refilled with normal saline for a second cycle of voiding and imaging, without the need of a second administration

Storage

Unreconstituted kit: Store at room temperature 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

Reconstituted suspension: May store at room temperature for up to 3 hr; does not contain antimicrobial preservative