Drug Detail:Definity rt (Perflutren [ per-floo-tren ])
Drug Class: Ultrasound contrast media
Highlights of Prescribing Information
DEFINITY RT (Perflutren Lipid Microsphere) Injectable Suspension, for intravenous use
Initial U.S. Approval: 2001
WARNING: SERIOUS CARDIOPULMONARY REACTIONS
See full prescribing information for complete boxed warning
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following perflutren-containing microsphere administration (5.1). Most serious reactions occur within 30 minutes of administration.
- Assess all patients for the presence of any condition that precludes DEFINITY RT administration (4).
- Always have resuscitation equipment and trained personnel readily available.
Recent Major Changes
| Warnings and Precautions, Pain Episodes in Patients with Sickle Cell Disease (5.5) | 6/2023 |
Indications and Usage for Definity RT
DEFINITY RT is an ultrasound contrast agent indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. (1)
Definity RT Dosage and Administration
DEFINITY RT may be injected by either an intravenous bolus or infusion. The maximum dose is either two bolus doses or one single intravenous infusion. (2.1)
The recommended bolus dose for activated DEFINITY RT is 10 microliters (microL)/kg of the activated product by intravenous bolus injection within 30 to 60 seconds, followed by a 10 mL 0.9% Sodium Chloride Injection, USP flush. If necessary, a second 10 microliters (microL)/kg dose followed by a second 10 mL 0.9% Sodium Chloride Injection, USP flush may be administered 30 minutes after the first injection to prolong contrast enhancement. (2.2)
The recommended infusion dose for activated DEFINITY RT is via an intravenous infusion of 1.3 mL added to 50 mL of preservative-free 0.9% Sodium Chloride Injection, USP. The rate of infusion should be initiated at 4 mL/minute, but titrated as necessary to achieve optimal image enhancement, not to exceed 10 mL/minute. (2.2)
See Full Prescribing Information for instructions on preparation and administration.
Dosage Forms and Strengths
DEFINITY RT is supplied as a single patient use 2 mL RFID-tagged clear glass vial containing colorless, uniformly clear to translucent (hazy) viscous solution in packages of twenty (20) single patient use vials. (3)
Contraindications
Do not administer DEFINITY RT to patients with known or suspected: Hypersensitivity to perflutren lipid microsphere or its components, such as polyethylene glycol (PEG). (4)
Warnings and Precautions
Serious cardiopulmonary reactions, including fatalities, have occurred during or following perflutren-containing microsphere administration. (5.1)
Serious acute hypersensitivity reactions have occurred in patients with no prior exposure to perflutren-containing microsphere products, including patients with prior hypersensitivity reaction(s) to PEG. (5.2, 6)
Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY RT administration and monitor all patients for acute reactions. (5.1, 5.2)
Pain episodes in patients with sickle cell disease. (5.5)
Adverse Reactions/Side Effects
The most common adverse reactions (≥0.5%) are headache, back/renal pain, flushing, nausea, chest pain, injection site reactions, and dizziness. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Lantheus Medical Imaging, Inc. at 1-800-362-2668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 6/2023
Full Prescribing Information
WARNING: SERIOUS CARDIOPULMONARY REACTIONS
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following perflutren-containing microsphere administration [see Warnings and Precautions (5.1)]. Most serious reactions occur within 30 minutes of administration.
- Assess all patients for the presence of any condition that precludes DEFINITY RT administration [see Contraindications (4)].
- Always have resuscitation equipment and trained personnel readily available.
1. Indications and Usage for Definity RT
Activated DEFINITY RT (Perflutren Lipid Microsphere) Injectable Suspension is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border.
2. Definity RT Dosage and Administration
2.1 Important Administration Instructions
- DEFINITY RT is intended for administration only after activation in the VIALMIX RFID apparatus. Before injection, this product must be activated, diluted, and prepared according to the instructions outlined below. The VIALMIX RFID apparatus should be ordered from Lantheus Medical Imaging, 331 Treble Cove Road, North Billerica, MA, 01862. For customer orders call 1-800-299-3431.
- 13mm ViaLok (packaged separately) must be used in the dilution process of Definity RT.
- DEFINITY RT may be injected by either an intravenous bolus or infusion. Do not administer DEFINITY RT by intra-arterial injection [see Warnings and Precautions (5.3)].
- The maximum dose is either two bolus doses or one single intravenous infusion. The safety of bolus and infusion dosing in combination or in sequence, has not been studied.
2.3 Imaging Guidelines
After baseline non-contrast echocardiography is completed, set the mechanical index for the ultrasound device at 0.8 or below [see Warnings and Precautions (5.4)]. Then inject activated DEFINITY RT (as described above) and begin ultrasound imaging immediately. Evaluate the activated DEFINITY RT echocardiogram images in combination with the non-contrast echocardiogram images.
In a crossover trial of 64 patients randomized to both bolus and infusion using DEFINITY, the duration of clinically useful contrast enhancement for fundamental imaging was approximately 3.4 minutes after a 10 microL/kg bolus and was approximately 7.1 minutes during the continuous infusion of 1.3 mL activated DEFINITY in 50 mL 0.9% Sodium Chloride Injection, USP at a rate of 4 mL/min.
2.4 DEFINITY RT Activation, Preparation and Handling Instructions
There are two formulations of perflutren lipid microspheres that have differences concerning storage and preparation. Follow the preparation and storage procedures, as well as directions for activation of DEFINITY RT carefully and adhere to strict aseptic procedures during preparation.
- Activate DEFINITY RT by shaking the vial for 45 seconds using a VIALMIX RFID device.
Note: illustrations of this procedure are contained in the VIALMIX RFID User's Guide.
Do not use this drug unless it has completed a full 45 second activation cycle in the VIALMIX RFID. DEFINITY RT will not be properly activated unless the full 45 second activation cycle is completed. 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 DEFINITY RT vial (see step 2). A VIALMIX RFID that is not functioning properly must never be used. Only use a vial activated from a properly functioning VIALMIX RFID. Refer to the VIALMIX RFID User's Guide to ensure that a properly functioning VIALMIX RFID is used. - Obtain a syringe containing 1.4 mL preservative-free 0.9% Sodium Chloride Injection, USP.
- Attach the syringe containing 1.4 mL preservative-free 0.9% Sodium Chloride Injection, USP to the 13mm ViaLok luer-lok hub. Add 1.4 mL of preservative-free 0.9% Sodium Chloride Injection, USP to the activated DEFINITY RT vial. Do not inject air into the DEFINITY RT vial.
- With the 13mm ViaLok still inserted and syringe attached, rapidly swirl the upright vial for 10 seconds to mix the contents. Activated and diluted DEFINITY RT appears as a milky white homogenous suspension with a presence of foam/bubbles.
- The product must be used within 5 minutes of dilution. If not used within 5 minutes the microspheres should be resuspended by rapidly swirling the upright vial for 10 seconds before the product is withdrawn in a syringe.
- The activated DEFINITY RT may be used for up to 4 hours from the time of dilution, with the 13mm ViaLok still attached, but only after the microspheres are resuspended by rapidly swirling the upright vial for 10 seconds.
- If not used immediately, the activated, diluted DEFINITY RT can be stored at room temperature 20° to 25°C (68° to 77°F) in the original product vial with the 13mm 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.
- Invert the vial and withdraw the activated milky white suspension through the 13mm ViaLok into the syringe. Do not inject air into the DEFINITY RT vial.
- Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe.
- For bolus dosing, withdraw appropriate volume based on patient weight (kg) for administration. For infusion dosing, dilute 1.3 mL Definity RT in 50 mL of preservative-free 0.9% Sodium Chloride Injection, USP. [see Dosage and Administration ( 2.2)].
3. Dosage Forms and Strengths
DEFINITY RT is supplied as a single patient use 2 mL RFID-tagged clear glass vial containing a colorless, uniformly clear to translucent (hazy) viscous solution in packages of twenty (20) single patient use vials.
Prior to activation, the headspace of each vial contains 6.52 mg/mL octafluoropropane and the viscous solution contains 3.75 mg/mL of a lipid blend. After activation and dilution with 0.9% Sodium Chloride Injection, USP, each vial contains a maximum of 1.2 × 1010 perflutren lipid microspheres, and about 80 microL/mL (0.65 mg/mL) octafluoropropane [see Description (11)].
4. Contraindications
Do not administer DEFINITY RT to patients with known or suspected:
- Hypersensitivity to perflutren lipid microsphere or its components, such as polyethylene glycol (PEG) [see Warnings and Precautions (5.2) and Description (11)].
5. Warnings and Precautions
5.1 Serious Cardiopulmonary Reactions
Serious cardiopulmonary reactions including fatalities have occurred uncommonly during or shortly following perflutren-containing microsphere administration, typically within 30 minutes of administration. The risk for these reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias). Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY RT administration and monitor all patients for acute reactions.
The reported reactions include: fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, and convulsions [see Adverse Reactions (6)].
5.2 Hypersensitivity Reactions
In postmarketing use, serious hypersensitivity reactions were observed during or shortly following perflutren-containing microsphere administration including:
Anaphylaxis, with manifestations that may include death, shock, bronchospasm, 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 have occurred in patients with no prior exposure to perflutren-containing microsphere products. DEFINITY RT contains PEG. There may be increased risk of serious reactions including death in patients with prior hypersensitivity reaction(s) to PEG [see Adverse Reactions (6.2) and Description (11)]. 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 DEFINITY RT administration and monitor all patients for hypersensitivity reactions.
5.3 Systemic Embolization
When administering DEFINITY RT to patients with a cardiac shunt, the microspheres can bypass filtering by the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following DEFINITY RT administration. DEFINITY RT is only for intravenous administration; do not administer DEFINITY RT by intra-arterial injection [see Dosage and Administration (2.1)].
5.4 Ventricular Arrhythmia Related to High Mechanical Index
High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. DEFINITY RT is not recommended for use at mechanical indices greater than 0.8 [see Dosage and Administration (2)].
5.5 Pain Episodes in Patients with Sickle Cell Disease
In postmarketing reports, acute pain episodes shortly following DEFINITY administration have been reported in patients with sickle cell disease (SCD). The pain episodes included moderate to severe back pain and vaso-occlusive crisis [see Adverse Reactions (6.2)]. If a patient with sickle cell disease experiences new or worsening pain, discontinue DEFINITY.
6. Adverse Reactions/Side Effects
The following serious adverse reactions are described elsewhere in the labeling:
- Serious Cardiopulmonary Reactions [see Warnings and Precautions (5.1)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
- Pain Episodes in Patients with Sickle Cell Disease [see Warnings and Precautions (5.5)]
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.
A total of 1716 subjects were evaluated in pre-market clinical trials of activated DEFINITY. In this group, 1063 (61.9%) were male and 653 (38.1%) were female, 1328 (77.4%) were White, 258 (15.0%) were Black, 74 (4.3%) were Hispanic, and 56 (3.3%) were classified as other racial or ethnic groups. The mean age was 56.1 years (range 18 to 93). Of these, 144 (8.4%) had at least one adverse reaction (Table 1). There were 26 serious adverse events and 15 (0.9%) subjects discontinued because of an adverse event.
6.2 Postmarketing Experience
In a prospective, multicenter, open-label registry of 1053 patients receiving DEFINITY in routine clinical practice, heart rate, respiratory rate, and pulse oximetry were monitored for 30 minutes after DEFINITY administration. No deaths or serious adverse reactions were reported, suggesting that these reactions are unlikely to occur at a rate of more than 0.3% when DEFINITY is used according to recommendations.
The following adverse reactions have been identified during the post-marketing use of perflutren and PEG-containing microsphere products. 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.
Fatal cardiopulmonary and hypersensitivity reactions and other serious but non-fatal adverse reactions were uncommonly reported. These reactions typically occurred within 30 minutes of DEFINITY 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)]
Reported reactions included:
8. Use In Specific Populations
8.4 Pediatric Use
The safety and effectiveness of activated DEFINITY RT have not been established in the pediatric population.
The safety of injecting activated DEFINITY RT in neonates and infants with immature pulmonary vasculature has not been studied.
The pharmacokinetics of activated DEFINITY RT in pediatric subjects has not been studied.
8.5 Geriatric Use
In clinical trials, the overall incidence of adverse reactions was similar for the <65 year age group and the ≥65 year age group. Of the total number of subjects in clinical trials of DEFINITY, 144 (33%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
11. Definity RT Description
DEFINITY RT (Perflutren Lipid Microsphere) Injectable Suspension is an ultrasound contrast agent. The DEFINITY RT vial contains components that upon activation and dilution yield perflutren lipid microspheres. The unactivated vial contains a colorless, uniformly clear to translucent (hazy), viscous, sterile, non-pyrogenic solution, which upon activation with the aid of a VIALMIX RFID and dilution with 0.9% Sodium Chloride Injection, USP, provides a homogeneous, hypertonic, milky white injectable suspension of perflutren lipid microspheres. The suspension of activated DEFINITY RT is administered by intravenous injection.
The perflutren lipid microspheres are composed of octafluoropropane encapsulated in an outer lipid shell consisting of (R) – hexadecanoic acid, 1-[(phosphonoxy)methyl]-1,2-ethanediyl ester, monosodium salt (abbreviated DPPA); (R) - 4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1-oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphapentacosan-1-aminium, 4-oxide, inner salt (abbreviated DPPC); and (R)- ∝-[6-hydroxy-6-oxido-9-[(1-oxohexadecyl)oxy]-5,7,11-trioxa-2-aza-6-phosphahexacos-1-yl]- ω-methoxypoly(ox-1,2-ethanediyl), monosodium salt; commonly called N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3- phosphatidylethanolamine, monosodium salt (abbreviated MPEG5000 DPPE).
Octafluoropropane is chemically characterized as 1,1,1,2,2,3,3,3-octafluoropropane. It has a molecular weight of 188, empirical formula of C3F8 and has the following structural formula:
DPPA has a molecular weight of 670, empirical formula of C35H68O8PNa, and following structural formula:
DPPC has a molecular weight of 734, empirical formula of C40H80NO8P, and following structural formula:
MPEG5000 DPPE has an approximate molecular weight of 5750 represented by empirical formula C265H527NO123PNa, contains <100ppm Ca2+ and the following structural formula:
Prior to activation, the DEFINITY RT vial contains 6.52 mg/mL octafluoropropane in the headspace which is confirmed by positive IR spectroscopic testing in every vial. Each mL of the viscous solution contains 3.75 mg lipid blend (consisting of 0.225 mg DPPA, 2.005 mg DPPC, and 1.520 mg MPEG5000 DPPE), 517.5 mg propylene glycol, 631 mg glycerin, 0.370 mg anhydrous sodium acetate, and 0.030 mg glacial acetic acid. The pH is 5.2 to 6.4. DEFINITY RT does not contain bacterial preservative.
After activating the contents of the vial in a VIALMIX RFID and diluting with 1.4 mL of preservative-free 0.9% Sodium Chloride, Injection, USP, each mL of the milky white suspension contains 0.045 mg DPPA, 0.401 mg DPPC, 0.304 mg MPEG5000 DPPE, 0.074 mg anhydrous sodium acetate, 0.006 mg glacial acetic acid, a maximum of 1.2 × 1010 perflutren lipid microspheres, and about 80 microL/mL (0.65 mg/mL) octafluoropropane. The microsphere particle size parameters are listed in Table 2 below:
| Microsphere particle size parameters | |
| Mean diameter range | 1.1 µm – 3.3 µm |
| Percent less than 10 µm | 98% |
| Maximum diameter | 20 µm |
12. Definity RT - Clinical Pharmacology
12.1 Mechanism of Action
Perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. These physical acoustic properties of activated DEFINITY RT 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 DEFINITY 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.
13. Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies with activated DEFINITY have not been performed to evaluate carcinogenic potential. Evidence of genotoxicity was not found in the following studies with activated DEFINITY: 1) bacterial mutagenesis assay (Ames assay), 2) in vitro mammalian mutagenesis assay, 3) in vitro human lymphocyte chromosome aberration assay, and 4) in vivo rat micronucleus assay.
Impairment of male or female fertility was not observed in rats and rabbits treated with activated DEFINITY at doses up to 24 and 15 times the human dose based on body surface area (in rats and rabbits respectively).
14. Clinical Studies
14.2 Pulmonary Hemodynamic Effects
The impact of DEFINITY on pulmonary hemodynamics was explored in a prospective, open-label study of patients with normal (≤ 35 mmHg, 16 patients) and elevated (> 35 mmHg, ≤ 75 mmHg, 16 patients) pulmonary artery systolic pressure undergoing right heart catheterization. Patients with pulmonary artery systolic pressure greater than 75 mmHg were excluded from this study. Systemic hemodynamic parameters and ECGs were also evaluated. No clinically important pulmonary hemodynamic, systemic hemodynamic, or ECG changes were observed. This study did not assess the effect of DEFINITY on visualization of cardiac or pulmonary structures.
16. How is Definity RT supplied
16.1 How Supplied
DEFINITY RT is supplied as a single patient use 2 mL clear glass Radio Frequency Identification (RFID)-tagged vial containing a colorless, uniformly clear to translucent (hazy) viscous solution in packages of twenty (20) single patient use vials.
- One (1) 2 mL RFID-tagged vial - NDC (11994-017-01)
- Twenty (20) 2 mL RFID-tagged vials per kit - NDC (11994-017-20)
16.2 Storage and Handling
Store at Room Temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Regarding interference with medical devices, the RFID tag and VIALMIX RFID unit meets the IEC 60601-1-2 requirements for emission and immunity standards for medical devices.
| DEFINITY RT
perflutren injection, suspension |
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| Labeler - Lantheus Medical Imaging, Inc. (176786812) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Samsung Biologics Co, LTD | 557810567 | MANUFACTURE(11994-017) , ANALYSIS(11994-017) | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Lantheus Medical Imaging, Inc. | 176786812 | ANALYSIS(11994-017) , MANUFACTURE(11994-017) , PACK(11994-017) , LABEL(11994-017) | |
