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  • CLASSES

    Ultrasound Agents

    BOXED WARNING

    Acute myocardial infarction, cardiopulmonary reaction, heart failure, ventricular arrhythmias

    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. 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.

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous ultrasound radiopaque contrast agent
    Used for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular border
    Associated with serious cardiopulmonary reactions although uncommonly

    COMMON BRAND NAMES

    Definity, Definity RT

    HOW SUPPLIED

    Definity/Perflutren Lipid Microspheres Intravenous Inj Susp: 2mL

    DOSAGE & INDICATIONS

    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 microliters/kg IV. May administer a second 10 microliters/kg dose 30 minutes after the first injection to prolong contrast enhancement if needed. The safety of bolus and infusion dosing in combination or in sequence, has not been studied.

    Continuous Intravenous Infusion dosage
    Adults

    4 mL/minute continuous IV infusion, initially. Titrate as necessary to achieve optimal image enhancement. Max: 10 mL/minute. The safety of bolus and infusion dosing in combination or in sequence has not been studied.

    MAXIMUM DOSAGE

    Adults

    Either two 10 microliters/kg IV bolus doses or a single continuous IV infusion.

    Geriatric

    Either two 10 microliters/kg IV bolus doses or a single continuous IV infusion.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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 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 use unless the vial has completed a full 45-second activation cycle. Error messages will display if the vial is not properly activated. Do not reactivate the vial if VialMix or VialMix RFID did not properly activate the vial. Never reactivate a successfully activated vial. Do not use a VialMix or VialMix RFID that is not functioning properly.
    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.[46931]
     
    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 use unless the vial has completed a full 45-second activation cycle. Error messages will display if the vial is not properly activated. Do not reactivate the vial if VialMix RFID did not properly activate the vial. Never reactivate a successfully activated vial. Do not use a VialMix RFID that is not functioning properly.
    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.
     
    Administration
    After baseline non-contrast echocardiography is completed, set the mechanical index for the ultrasound device at 0.8 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.
    The safety of bolus and infusion dosing in combination or in sequence, has not been studied.[46931]
     
    Bolus IV Injection:
    Administer within 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 was approximately 3.4 minutes after the bolus dose.[46931]
     
    IV Infusion:
    Add 1.3 mL of perflutren lipid microspheres to 50 mL of preservative-free 0.9% Sodium Chloride Injection.
    The duration of clinically useful contrast enhancement for fundamental imaging was approximately 7.1 minutes during the continuous infusion.[46931]

    STORAGE

    Definity :
    - Refrigerate (between 36 and 46 degrees F)
    Definity RT:
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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 ase polyethylene glycol (PEG). 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 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.

    Intraarterial administration

    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.

    Acute myocardial infarction, cardiopulmonary reaction, heart failure, ventricular arrhythmias

    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. 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.

    Arteriovenous shunt

    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.

    Pregnancy

    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.[46931]

    Breast-feeding

    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.[46931]

    ADVERSE REACTIONS

    Severe

    cardiopulmonary reaction / Rapid / 1.1-1.1
    bradycardia / Rapid / 0-0.5
    agranulocytosis / Delayed / 0-0.5
    hearing loss / Delayed / 0-0.5
    visual impairment / Early / 0-0.5
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    atrial fibrillation / Early / Incidence not known
    seizures / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    coma / Early / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 0.8-0.8
    dyspnea / Early / 0-0.5
    sinus tachycardia / Rapid / 0-0.5
    palpitations / Early / 0-0.5
    hypotension / Rapid / 0-0.5
    hypoxia / Early / 0-0.5
    hypertension / Early / 0-0.5
    hot flashes / Early / 0-0.5
    hypertonia / Delayed / 0-0.5
    leukopenia / Delayed / 0-0.5
    eosinophilia / Delayed / 0-0.5
    hematoma / Early / 0-0.5
    conjunctivitis / Delayed / 0-0.5
    erythema / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    headache / Early / 2.3-2.3
    back pain / Delayed / 1.2-1.2
    flushing / Rapid / 1.1-1.1
    nausea / Early / 1.0-1.0
    injection site reaction / Rapid / 0.6-0.6
    dizziness / Early / 0.6-0.6
    urticaria / Rapid / 0-0.5
    rash / Early / 0-0.5
    pruritus / Rapid / 0-0.5
    syncope / Early / 0-0.5
    fever / Early / 0-0.5
    fatigue / Early / 0-0.5
    paresthesias / Delayed / 0-0.5
    vertigo / Early / 0-0.5
    vomiting / Early / 0-0.5
    dyspepsia / Early / 0-0.5
    diarrhea / Early / 0-0.5
    dysgeusia / Early / 0-0.5
    xerostomia / Early / 0-0.5
    abdominal pain / Early / 0-0.5
    leukocytosis / Delayed / 0-0.5
    arthralgia / Delayed / 0-0.5
    rhinitis / Early / 0-0.5
    cough / Delayed / 0-0.5
    pharyngitis / Delayed / 0-0.5
    hyperhidrosis / Delayed / 0-0.5
    xerosis / Delayed / 0-0.5
    hypoesthesia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    agitation / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Perflutren Lipid Microspheres products.

    PREGNANCY AND LACTATION

    Pregnancy

    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.[46931]

    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.[46931]

    MECHANISM OF ACTION

    Perflutren lipid microspheres help supply additional contrast to enhance ultrasound imaging. It 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.

    PHARMACOKINETICS

    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 < 10 micrometers (maximum diameter 20 micrometers). Pharmacokinetics of octafluropropane gas (OFP) was studied in 8 healthy subjects after IV administration of 50 microL/kg. OFP binding to plasma proteins or partitioning into blood cells has not been studied; however, OFP protein binding is expected to be minimal due to a low partition coefficient into whole blood. OFP 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 OFP is via the lungs. OFP 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.