Perflutren lipid microsphere is an intravenous ultrasound radiopaque contrast agent 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 border. Perflutren is octafluoropropane, a fluorocarbon gas encapsulated in an outer lipid shell. During an ultrasound examination, the difference in density between the gas-filled bubbles and the blood around them creates an increased level of contrast visible in the resulting ultrasound image. Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or shortly after perflutren-containing microsphere administration; the risk for these reactions may be increased among patients with unstable cardiopulmonary conditions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-There are 2 different formulations of perflutren lipid microspheres, refrigerated or room temperature, that have differences concerning storage and preparation. Follow the preparation and storage procedures, as well as directions for activation, carefully.
Activation and Preparation of Refrigerated Product
-Allow the vial to warm to room temperature before starting the activation procedure.
-Refrigerated perflutren lipid microspheres is intended for administration only after activation in a VialMix or VialMix RFID apparatus.
-Certain vials are radio frequency identification (RFID)-tagged, which allows for the exchange of product information such as activation time and activation rate. VialMix RFID will only activate RFID-tagged vials. The function of the RFID technology is not dependent on vial orientation as it placed in the VialMix RFID. If the RFID tag is damaged or otherwise non-functional, the VialMix RFID will notify the user. Discard the non-functional RFID-tagged vial. Do not operate any part of the VialMix RFID and RFID-tagged vials within 6 inches of a pacemaker or defibrillator.
-Activate the vial by shaking it for 45 seconds using a VialMix or VialMix RFID device. Do not reactivate the vial if VialMix or VialMix RFID did not properly activate the vial. Never reactivate a successfully activated vial. Refer to VialMix RFID user's guide for activation procedures and properly functioning VialMix RFID.
-Immediately after activation, the product appears as a milky white suspension.
-If the drug is not used within 5 minutes of activation, resuspend the microspheres by 10 seconds of hand agitation by inverting the vial before the product is withdrawn into a syringe.
-Invert the vial and withdraw the suspension from the middle of the liquid in the inverted vial using the Intellipin (Dispensing Pin), the PINSYNC (vented vial adapter 13 mm), or 18- to 20-gauge syringe needle. Do not inject air into the vial.
-Use the product immediately after its withdrawal from the vial; do not allow the product stand in the syringe.
-Storage: Store the activated product at room temperature in the original vial for up to 12 hours from the time of activation.
Activation and Preparation of Room Temperature (RT) Product
-RT perflutren lipid microspheres is intended for administration only after activation in a VialMix RFID apparatus.
-RT vials are radio frequency identification (RFID)-tagged, which allows for the exchange of product information such as activation time and activation rate. VialMix RFID will only activate RFID-tagged vials. The function of the RFID technology is not dependent on vial orientation as it placed in the VialMix RFID. If the RFID tag is damaged or otherwise non-functional, the VialMix RFID will notify the user. Discard the non-functional RFID-tagged vial. Do not operate any part of the VialMix RFID and RFID-tagged vials within 6 inches of a pacemaker or defibrillator.
-Activate the vial by shaking it for 45 seconds using a VialMix RFID device. Do not reactivate the vial if VialMix RFID did not properly activate the vial. Never reactivate a successfully activated vial. Refer to VialMix RFID user's guide for activation procedures and properly functioning VialMix RFID.
-Immediately after activation, but no more than 15 minutes, place the activated vial in the upright position and remove the flip top cap. Insert the provided 13 mm ViaLok (vented vial access device) into the center of the rubber stopper and push down until properly engaged and locked onto the vial.
-Obtain a syringe containing 1.4 mL of preservative-free 0.9% Sodium Chloride Injection and attach to the 13 mm ViaLok luer-lok hub. Add 1.4 mL of preservative-free 0.9% Sodium Chloride Injection to the activated vial. Do not inject air into the vial.
-With the 13 mm ViaLok still inserted and syringe attached, rapidly swirl the upright vial for 10 seconds to mix the contents. The product appears as a milky white homogenous suspension with a presence of foam or bubbles.
-If the drug is not used within 5 minutes of dilution, resuspend the microspheres by rapidly swirling the upright vial for 10 seconds before the product is withdrawn into a syringe.
-Invert the vial and withdraw the suspension through the 13 mm ViaLok into the syringe. Do not inject air into the vial.
-Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe.
-Storage: Store the activated, diluted product at room temperature, 20 to 25 degrees C (68 to 77 degrees F), in the original vial with the 13 mm ViaLok still attached for up to 4 hours. A sterile syringe or cap should be attached to the Luer fitting on the ViaLok until use.
Administration
-After baseline non-contrast echocardiography is completed, set the mechanical index for the ultrasound device:
--Adults: 0.8 or below
-Pediatrics: 0.3 or below
-Then inject perflutren lipid microspheres and begin ultrasound imaging immediately. Evaluate the perflutren lipid microspheres echocardiogram images in combination with the non-contrast echocardiogram images.
-Adults: May administer by either an IV bolus or infusion. Do not administer the bolus and infusion dosing in combination or in sequence.
-Pediatrics: Administer by IV bolus injection only.
IV Bolus Injection
-Adults:
--Administer over 30 to 60 seconds, followed by a 10 mL 0.9% Sodium Chloride Injection flush.
-The duration of clinically useful contrast enhancement for fundamental imaging following a 10 microL/kg bolus was approximately 3.4 minutes.
-Pediatrics:
--Administer over 30 to 60 seconds, followed by a 5 mL 0.9% Sodium Chloride Injection flush.
-The duration of clinically useful contrast enhancement for fundamental imaging following a 3 microL/kg and 5 microL/kg bolus was approximately 2.7 minutes and 3.9 minutes, respectively.
IV Infusion
-Add 1.3 mL of perflutren lipid microspheres to 50 mL of preservative-free 0.9% Sodium Chloride Injection.
-Initiate infusion at 4 mL/minute, titrating the infusion rate as necessary to achieve optimal image enhancement, not to exceed 10 mL/minute.
-The duration of clinically useful contrast enhancement for fundamental imaging was approximately 7.1 minutes during the continuous infusion.
Serious hypersensitivity or anaphylactoid reactions have been noted during or shortly after perflutren lipid microspheres administration, typically within 30 minutes. These reactions include anaphylaxis, with manifestations that may include death, anaphylactic shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, localized, peripheral edema), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash (0.5% or less), urticaria (0.5% or less), pruritus (0.5% or less), flushing (1%), and erythema.
Serious cardiopulmonary reaction (1.1%, n = 1,716), including fatalities, have been reported during or shortly after (within 30 minutes) perflutren-containing microsphere administration. Reported reactions include fatal cardiac arrest, fatal respiratory arrest, shock, syncope (up to 0.5%), symptomatic arrhythmias (atrial fibrillation, sinus tachycardia (up to 0.5%), bradycardia (up to 0.5%), supraventricular tachycardia (SVT), ventricular fibrillation, ventricular tachycardia), hypertension (up to 0.5%), hypotension (up to 0.5%), dyspnea (up to 0.5%), hypoxia (up to 0.5%), chest pain (unspecified) (0.8%), respiratory distress, stridor, wheezing, loss of consciousness, and seizures. Abnormal ECGs and palpitations have also been reported in up to 0.5% of patients.
Injection site reaction was reported in 0.6% of patients receiving perflutren lipid microspheres.
General adverse events have been reported with the use of perflutren lipid microspheres including renal/back pain (1.2%). Other adverse events reported in 0.5% or less of patients include fatigue, fever, hot flashes, pain, rigors, and albuminuria. Acute pain episodes (i.e., moderate to severe back pain and vaso-occlusive crisis) occurring soon after administration of perflutren lipid microspheres have been reported in persons with sickle cell disease in postmarking surveillance. Discontinue perflutren lipid microspheres if persons with sickle cell disease develop new or worsening pain.
Nervous system adverse reactions have been reported with the use of perflutren lipid microspheres and include headache (2.3%) and dizziness (0.6%). Other adverse events reported in 0.5% or less of patients include leg cramps, hypertonia, vertigo, and paresthesias. Additionally, coma, transient ischemic attack, agitation, tremor, and blurred vision have been reported rarely.
Nausea was reported in 1% of patients receiving perflutren lipid microspheres. Other adverse events reported in 0.5% or less of patients include dyspepsia, dry mouth (xerostomia), tongue disorder, toothache, abdominal pain, diarrhea, vomiting, and dysgeusia.
Hematologic and bleeding adverse events reported in 0.5% or less of patients receiving perflutren lipid microspheres include agranulocytosis, leukocytosis, leukopenia, eosinophilia, and hematoma.
Arthralgia was reported in 0.5% or less of patients receiving perflutren lipid microspheres.
Cough, pharyngitis, and rhinitis were reported in 0.5% or less of patients receiving perflutren lipid microspheres.
Decreased hearing or hearing loss, conjunctivitis, and visual impairment were reported in 0.5% or less of patients receiving perflutren lipid microspheres.
Rash, erythematous rash, urticaria, pruritus, increased sweating (hyperhidrosis), and xerosis were reported in 0.5% or less of patients receiving perflutren lipid microspheres.
Do not give perflutren lipid microspheres via intraarterial administration. The direct entry of perflutren lipid microspheres into arterial circulation may result in significant toxicity such as microvascular occlusion and ischemia.
Perflutren lipid microspheres is contraindicated for use in individuals with a known or suspected history of hypersensitivity to perflutren lipid microspheres or its components, such as polyethylene glycol hypersensitivity. Serious hypersensitivity reactions, including anaphylaxis with manifestations that may include death, have been noted during or shortly after perflutren lipid microspheres administration. These reactions may develop in patients with no prior exposure to perflutren-containing microsphere products. There may be an increased risk of serious reactions, including death, in patients with prior hypersensitivity reactions to polyethylene glycol (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 perflutren lipid microspheres administration, and monitor all patients for hypersensitivity reactions.
Although uncommon, a serious cardiopulmonary reaction, including some fatal, has occurred during or shortly following the administration of perflutren lipid microspheres, typically within 30 minutes of administration. These reactions include fatal cardiac or respiratory arrest, shock, syncope, cardiac arrhythmias, hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, and convulsions. Patients at increased risk for these reactions include those with unstable cardiopulmonary conditions such as acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias. Ensure resuscitation equipment and trained personnel are readily available prior to perflutren lipid microspheres administration, and monitor all patients for acute reactions. Additionally, before contrast administration, adjust the ultrasound mechanical index value to 0.8 or lower for adults and 0.3 or lower for pediatrics. 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 caution when administering perflutren lipid microspheres to patients with an arteriovenous shunt. In these patients, microspheres can bypass filtering by the lung and directly enter the arterial circulation, which may result in significant toxicity such as microvascular occlusion and ischemia. Assess patients with shunts for embolic phenomena following administration of perflutren lipid microspheres.
Data from case reports with perflutren lipid microspheres use in human pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Perflutren lipid microspheres has a very short half-life; therefore, maternal use of the drug is not expected to result in clinically relevant fetal exposure. No adverse developmental outcomes were observed in pregnant rats or rabbits given perflutren lipid microspheres at doses up to 8- to 16-times, respectively, the maximum human recommended dose based on body surface area.
There are no data on the presence of perflutren lipid microspheres in human 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 perflutren lipid microspheres and any potential adverse effects on the breast-fed infant from perflutren lipid microspheres or the underlying maternal condition.
Acute pain episodes (i.e., moderate to severe back pain and vaso-occlusive crisis) occurring soon after administration of perflutren lipid microspheres have been reported in persons with sickle cell disease in postmarking surveillance. Discontinue perflutren lipid microspheres if persons with sickle cell disease develop new or worsening pain.
For use in echocardiography in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border:
Intravenous dosage:
Adults: 10 microL/kg IV. May administer a second 10 microL/kg dose 30 minutes after the first injection to prolong contrast enhancement if needed. Do not administer the bolus and infusion dosing in combination or in sequence.
Infants, Children, and Adolescents: 3 microL/kg IV. May administer a second bolus dose of 3 to 5 microL/kg 30 minutes after the first injection to prolong contrast enhancement if needed.
Continuous Intravenous Infusion dosage:
Adults: 4 mL/minute continuous IV infusion, initially. Titrate as necessary to achieve optimal image enhancement. Max: 10 mL/minute. Do not administer the bolus and infusion dosing in combination or in sequence.
Maximum Dosage Limits:
-Adults
Either two 10 microL/kg IV bolus doses or a single continuous IV infusion (Max: 10 mL/minute).
-Geriatric
Either two 10 microL/kg IV bolus doses or a single continuous IV infusion (Max: 10 mL/minute).
-Adolescents
Two IV bolus doses (3 microL/kg, followed by 3 to 5 microL/kg)
-Children
Two IV bolus doses (3 microL/kg, followed by 3 to 5 microL/kg)
-Infants
Two IV bolus doses (3 microL/kg, followed by 3 to 5 microL/kg)
-Neonates
Safety and efficacy have not been established.
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 Perflutren Lipid Microspheres products.
Perflutren lipid microspheres help supply additional contrast to enhance ultrasound imaging. They exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. These physical acoustic properties of activated perflutren provide contrast enhancement of the left ventricular chamber and aid delineation of the left ventricular endocardial border during echocardiography.
In animal models the acoustic properties of activated perflutren lipid microspheres were established at or below a mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below a mechanical index of 0.8.
Perflutren lipid microspheres injection is administered intravenously. Human pharmacokinetic studies of the intact or degassed lipid microspheres have not been performed. The mean diameter range of the microsphere particles is 1.1-3.3 micrometers with 98% having a diameter of less than 10 micrometers (maximum diameter 20 micrometers). Pharmacokinetics of perflutren gas was studied in 8 healthy subjects after IV administration of 50 microL/kg. Perflutren gas binding to plasma proteins or partitioning into blood cells has not been studied; however, perflutren protein binding is expected to be minimal due to a low partition coefficient into whole blood. Perflutren is a stable gas that is not metabolized, but the phospholipid components of the microspheres are thought to be metabolized to free fatty acids. The main route of eliminate for perflutren is via the lungs. Perflutren was not detectable after 10 minutes in most subjects in either the blood or in expired air. The mean half-life was 1.3 minutes.
-Special Populations
Pediatrics
In a study in pediatric patients (n = 40; 1 month and older) undergoing echocardiography with a mechanical index of 0.3 or lower, left ventricular opacification with perflutren lipid microspheres was graded as adequate or full in 80% to 95% of patients (depending on view) at the 3 microL/kg dose and 85% to 88% of patients at the 5 microL/kg dose.
Other
Patients with Chronic Obstructive Pulmonary Disease (COPD)
In a study of 11 patients with COPD, the mean half-life of perflutren in the blood was 1.9 minutes with the total lung clearance similar to that of healthy subjects.