WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: Serious acute hypersensitivity reactions have occurred. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY RT administration and monitor all patients for acute reactions. (5.2)Pain Episodes in Patients with Sickle Cell Disease: Discontinue DEFINITY RT for new or worsening pain. (5.5). Hypersensitivity Reactions: Serious acute hypersensitivity reactions have occurred. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY RT administration and monitor all patients for acute reactions. (5.2). Pain Episodes in Patients with Sickle Cell Disease: Discontinue DEFINITY RT for new or worsening pain. (5.5). 5.1Serious 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 (6.2)].. 5.2Hypersensitivity 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. DEFINITY RT is contraindicated in patients with known or suspected hypersensitivity to perflutren lipid microsphere or its components such as PEG [see Contraindications (4)]. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY RT administration and monitor all patients for hypersensitivity reactions.. 5.3Systemic Embolization. When administering DEFINITY RT to patients with 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 and must not be administered by intra-arterial injection [see Dosage and Administration (2.1,2.2,2.3)].. 5.4Ventricular 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. The maximum recommended mechanical index for use with DEFINITY RT is 0.8 in adult patients and 0.3 in pediatric patients [see Dosage and Administration (2.4)].. 5.5Pain Episodes in Patients with Sickle Cell Disease. In postmarketing reports, acute pain episodes shortly following DEFINITY RT 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 patient with sickle cell disease experiences new or worsening pain, discontinue DEFINITY RT.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and effectiveness of DEFINITY RT have been established for use in pediatric patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve delineation of the left endocardial border. Use of DEFINITY RT for this indication is supported by evidence from adequate and well-controlled studies in adults [see Clinical Studies (14)], pharmacodynamic and safety study in 40 pediatric patients month of age and older [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2)], and published studies in 149 patients years to 24 years of age [see Adverse Reactions (6.1)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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)]. 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)]. 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. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions in AdultsSafety of DEFINITY RT was evaluated in total of 1,716 adult subjects who received DEFINITY, another formulation of perflutren lipid microspheres, in pre-market clinical trials. In this group, 1,063 (62%) were male and 653 (38%) were female, 1,328 (77%) were White, 258 (15%) were Black or African American, 74 (4%) were Hispanic, and 56 (3%) were classified as other racial or ethnic groups. The mean age was 56 years (range 18 to 93). Among the 1,716 subjects, 19 (1.1%) suffered serious cardiopulmonary adverse reactions.Adverse reactions that led to discontinuation in total of 15 (0.9%) subjects receiving DEFINITY in the clinical trials included urticaria, pruritus, dizziness, chest pain, dyspnea, and back pain.Table summarizes the most common adverse reactions occurring at >=0.5%.Table 1Adverse Reactions Occurring in >=0.5% of All DEFINITY-Treated SubjectsDEFINITY (N=1716)Total Number of Adverse Reactions269Total Number of Subjects with an Adverse Reaction144(8.4%)Body system Preferred termn(%)N=Sample size 1716 subjects who received activated DEFINITYn=Number of subjects reporting at least one Adverse ReactionApplication Site Disorders11(0.6) Injection Site Reactions11(0.6)Body as Whole41(2.4) Back/renal pain20(1.2) Chest pain13(0.8)Central and peripheral nervous system disorder54(3.1) Headache40(2.3) Dizziness11(0.6)Gastrointestinal system31(1.8) Nausea17(1.0)Vascular (extracardiac) disorders19(1.1) Flushing19(1.1)Other adverse reactions that occurred in <0.5% of the activated DEFINITY-dosed subjects were:Body as Whole: Fatigue, fever, hot flushes, pain, rigors, and syncopeCardiovascular: Abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension and hypotensionDigestive: Dyspepsia, dry mouth, tongue disorder, toothache, abdominal pain, diarrhea and vomitingHematology: Granulocytosis, leukocytosis, leukopenia, and eosinophiliaMusculoskeletal: ArthralgiaNervous System: Leg cramps, hypertonia, vertigo and paresthesiaPlatelet, Bleeding, and Clotting: HematomaRespiratory: Coughing, hypoxia, pharyngitis, rhinitis and dyspneaSpecial Senses: Decreased hearing, conjunctivitis, abnormal vision and taste perversionSkin: Pruritus, rash, erythematous rash, urticaria, increased sweating, and dry skinUrinary: Albuminuria. Adverse Reactions in Pediatric PatientsIn study of DEFINITY in 40 pediatric patients month of age and older, no new safety signals were observed [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2)].In published studies of DEFINITY in 149 patients years to 24 years of age (mean age 16.8 years; 56% male) clinically indicated for echocardiography, no additional safety signals were observed.. 6.2Postmarketing Experience. Adverse Reactions from Observational StudiesIn prospective, multicenter, open-label registry of 1,053 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.. Adverse Reactions from Postmarketing Spontaneous ReportsThe 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. CardiopulmonaryFatal 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.. Immune SystemAnaphylaxis, 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.. NeurologicComa, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue.. Blood and Lymphatic SystemAcute pain episodes including vaso-occlusive crisis in patients with sickle cell disease.

BOXED WARNING SECTION.

WARNING: SERIOUS CARDIOPULMONARY REACTIONS. Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following perflutren-containing microsphere administration. 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 [see Warnings and Precautions (5.1)].. 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 [see Warnings and Precautions (5.1)].. WARNING: SERIOUS CARDIOPULMONARY REACTIONSSerious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following perflutren-containing microsphere administration. 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 (5.1).. Assess all patients for the presence of any condition that precludes DEFINITY RT administration (4).. Always have resuscitation equipment and trained personnel readily available (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, and Impairment of Fertility. Studies with activated DEFINITY RT 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).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism 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 mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below mechanical index of 0.8.. 12.2 Pharmacodynamics. Contrast Enhancement Duration in AdultsIn crossover trial of 64 adult subjects randomized to both bolus and infusion, the duration of clinically useful contrast enhancement for fundamental imaging was approximately 3.4 minutes after 10 microL/kg bolus and was approximately 7.1 minutes during the continuous infusion of 1.3 mL activated DEFINITY in 50 mL saline at rate of mL/min.. Dose-Ranging and Contrast Enhancement Duration in Pediatric PatientsIn pharmacodynamic and safety study, DEFINITY was administered to 40 pediatric patients month of age and older clinically indicated for echocardiography (60% male; 10 patients were month to younger than year of age; patients were to years of age; 10 patients were to 10 years of age; 10 patients were 11 to 16 years of age; and patient was 17 years of age). Patients underwent echocardiography with mechanical index of <= 0.3 and received DEFINITY as series of sequential bolus injections (3 microL/kg and microL/kg) with each injection separated by approximately minutes. Patients had acceptable cardiac imaging at baseline. Left ventricular opacification with DEFINITY was graded as adequate or full in 80% to 95% of patients (depending on view) at the microL/kg dose and 85% to 88% of patients at the microL/kg dose [see Dosage and Administration (2.3)]. The mean duration of clinically useful contrast enhancement was approximately 2.7 minutes after bolus dose of microL/kg and 3.9 minutes after bolus dose of microL/kg.. Pulmonary Hemodynamic EffectsThe impact of DEFINITY on pulmonary hemodynamics was explored in 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.. 12.3Pharmacokinetics. Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of perflutren gas was evaluated in healthy subjects (n=8) after the intravenous administration of activated DEFINITY at 50 microL/kg (5 times the recommended dose).. DistributionPerflutren 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 its low partition coefficient into whole blood.. Elimination. MetabolismPerflutren is stable gas that is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids.. ExcretionPerflutren was not detectable after 10 minutes in most subjects either in the blood or in expired air. Perflutren concentrations in blood were shown to decline in mono-exponential fashion with mean half-life of 1.3 minutes in healthy subjects.. Specific Populations. Patients with Obstructive Pulmonary DiseaseThe pharmacokinetics of perflutren gas was evaluated in subjects (n=11) with chronic obstructive pulmonary disease (COPD). The mean half-life of perflutren in blood was 1.9 minutes. The total lung clearance of perflutren was similar to that in healthy subjects.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. Effectiveness and safety of DEFINITY RT were evaluated in four controlled clinical trials of DEFINITY, another formulation of perflutren lipid microsphere, (two open-label baseline controlled, unpaired blinded image evaluation studies and two identical placebo-controlled, unpaired blinded image evaluation studies) in 249 subjects who had two or more (of six) non-evaluable segments in either the apical 2- or 4-chamber view in non-contrast fundamental echocardiography.In this group, 154 (62%) were male and 95 (38%) were female; 183 (74%) were White, 38 (15%) were Black or African American, 21 (8%) were Hispanic, and (3%) were classified as other racial or ethnic groups. The mean age was 54 years (range 18 to 87).In the two open-label baseline controlled studies, total of 126 (67 in study and 59 in study B) subjects received bolus dose of 10 microL/kg activated DEFINITY. The outcome measures in these studies included the blinded assessment of ejection fraction (EF), endocardial border length (EBL) obtained by direct measurement, and qualitative assessment of wall motion.In the two placebo-controlled studies total of 123 subjects were randomized in 1:2 ratio to receive two intravenous bolus doses of either 0.9% Sodium Chloride Injection (placebo) or activated DEFINITY 10 microL/kg (17 placebo vs. 33 DEFINITY subjects and 24 placebo vs. 49 DEFINITY subjects, respectively). The outcome measure for assessing the effectiveness of DEFINITY was the blinded assessment of improvement in ventricular chamber enhancement (measured by videodensitometry at end-diastole and end-systole).. Endocardial Border LengthAs shown in Table 3, compared to baseline, single bolus dose of 10 microL/kg of activated DEFINITY increased the length of endocardial border that could be measured at both end-systole and end-diastole. The mean change in border length from baseline at end-diastole was statistically significant for all readers in the apical 4-chamber view and for out of readers for the apical 2-chamber view. The mean change in border length from baseline at end-systole was statistically significant for out of readers for the apical 4-chamber view and for out of readers for the apical 2-chamber view.. Ventricular Chamber EnhancementLeft ventricular chamber enhancement after an activated DEFINITY dose of 10 microL/kg was significantly increased from baseline compared to placebo in both views at the mid-ventricular and apical levels at end-diastole. Similar results were noted at end-systole, with the exception of the 4-chamber view.. Wall MotionIn retrospective analysis, in subset of subjects (n=12 to 47, depending on reader) having at least adjacent segments non-evaluable on non-contrast imaging, DEFINITY converted baseline non-evaluable image to an evaluable image in 58 to 91% of the subjects, depending on the reader. In the converted images, the accuracy of wall motion (i.e., normal versus abnormal) improved in 42 to 71% of the subjects, depending on the reader, however, improvement in the specific diagnostic accuracy (e.g., hypokinetic, akinetic etc.) was not established. Also, in 13 to 37% of the subjects, depending on the reader, DEFINITY was found to obscure the wall motion rendering the image non-evaluable.. Ejection FractionIn the baseline controlled studies, ejection fraction results were evaluated in comparison to MRI. The results were evaluated by blinded, independent radiologists. In these studies, although there was statistically significant increase in ventricular chamber enhancement, DEFINITY did not significantly improve the assessment of ejection fraction compared to the baseline images.Table 3MEAN (SD) ENDOCARDIAL BORDER LENGTH (CM) BY BOTH APICAL 2- AND 4-CHAMBER VIEWS AT END-SYSTOLE AND END-DIASTOLE BY STUDY, EVALUABLE SUBJECTSStudy/ViewEndocardial Border Length Blinded ReadMean(SD) at End-DiastoleMean(SD) at End-SystoleReader 1Reader 2Reader 1Reader 2Activated DEFINITY Bolus Dose 10 uL/kgStudy A: (N 67)Apical 2-chamber Baseline8.0(3.4)4.7(2.8)7.1(3.3) 4.3(2.6) Post-DEFINITY12.8(5.2)Significant change from baseline (paired t-test, p<0.05) 5.8(2.6) 10.6(5.0) 4.4(2.3)Apical 4-chamber Baseline8.1(3.3)4.5(2.6)7.6(3.2)4.5(2.7) Post-DEFINITY13.5(5.2) 6.8(3.3) 11.5(4.4) 5.3(3.1)Study B: (N 59)Apical 2-chamber Baseline4.3(2.6)7.8(5.3)4.1(2.4) 6.5(5.1) Post-DEFINITY5.7(4.7) 8.2(6.5)5.5(4.4) 6.9(6.3)Apical 4-chamber Baseline4.0(2.7)9.2(5.9)3.8(2.6)7.3(5.6) Post-DEFINITY7.1(5.5) 11.5(7.5) 5.9(5.3) 8.7(6.3).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions in AdultsSafety of DEFINITY RT was evaluated in total of 1,716 adult subjects who received DEFINITY, another formulation of perflutren lipid microspheres, in pre-market clinical trials. In this group, 1,063 (62%) were male and 653 (38%) were female, 1,328 (77%) were White, 258 (15%) were Black or African American, 74 (4%) were Hispanic, and 56 (3%) were classified as other racial or ethnic groups. The mean age was 56 years (range 18 to 93). Among the 1,716 subjects, 19 (1.1%) suffered serious cardiopulmonary adverse reactions.Adverse reactions that led to discontinuation in total of 15 (0.9%) subjects receiving DEFINITY in the clinical trials included urticaria, pruritus, dizziness, chest pain, dyspnea, and back pain.Table summarizes the most common adverse reactions occurring at >=0.5%.Table 1Adverse Reactions Occurring in >=0.5% of All DEFINITY-Treated SubjectsDEFINITY (N=1716)Total Number of Adverse Reactions269Total Number of Subjects with an Adverse Reaction144(8.4%)Body system Preferred termn(%)N=Sample size 1716 subjects who received activated DEFINITYn=Number of subjects reporting at least one Adverse ReactionApplication Site Disorders11(0.6) Injection Site Reactions11(0.6)Body as Whole41(2.4) Back/renal pain20(1.2) Chest pain13(0.8)Central and peripheral nervous system disorder54(3.1) Headache40(2.3) Dizziness11(0.6)Gastrointestinal system31(1.8) Nausea17(1.0)Vascular (extracardiac) disorders19(1.1) Flushing19(1.1)Other adverse reactions that occurred in <0.5% of the activated DEFINITY-dosed subjects were:Body as Whole: Fatigue, fever, hot flushes, pain, rigors, and syncopeCardiovascular: Abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension and hypotensionDigestive: Dyspepsia, dry mouth, tongue disorder, toothache, abdominal pain, diarrhea and vomitingHematology: Granulocytosis, leukocytosis, leukopenia, and eosinophiliaMusculoskeletal: ArthralgiaNervous System: Leg cramps, hypertonia, vertigo and paresthesiaPlatelet, Bleeding, and Clotting: HematomaRespiratory: Coughing, hypoxia, pharyngitis, rhinitis and dyspneaSpecial Senses: Decreased hearing, conjunctivitis, abnormal vision and taste perversionSkin: Pruritus, rash, erythematous rash, urticaria, increased sweating, and dry skinUrinary: Albuminuria. Adverse Reactions in Pediatric PatientsIn study of DEFINITY in 40 pediatric patients month of age and older, no new safety signals were observed [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2)].In published studies of DEFINITY in 149 patients years to 24 years of age (mean age 16.8 years; 56% male) clinically indicated for echocardiography, no additional safety signals were observed.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. DEFINTY RT is contraindicated in 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)]. Known or suspected hypersensitivity to perflutren lipid microsphere or its Components, such as polyethylene glycol (PEG) (4).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Contrast Enhancement Duration in AdultsIn crossover trial of 64 adult subjects randomized to both bolus and infusion, the duration of clinically useful contrast enhancement for fundamental imaging was approximately 3.4 minutes after 10 microL/kg bolus and was approximately 7.1 minutes during the continuous infusion of 1.3 mL activated DEFINITY in 50 mL saline at rate of mL/min.. Dose-Ranging and Contrast Enhancement Duration in Pediatric PatientsIn pharmacodynamic and safety study, DEFINITY was administered to 40 pediatric patients month of age and older clinically indicated for echocardiography (60% male; 10 patients were month to younger than year of age; patients were to years of age; 10 patients were to 10 years of age; 10 patients were 11 to 16 years of age; and patient was 17 years of age). Patients underwent echocardiography with mechanical index of <= 0.3 and received DEFINITY as series of sequential bolus injections (3 microL/kg and microL/kg) with each injection separated by approximately minutes. Patients had acceptable cardiac imaging at baseline. Left ventricular opacification with DEFINITY was graded as adequate or full in 80% to 95% of patients (depending on view) at the microL/kg dose and 85% to 88% of patients at the microL/kg dose [see Dosage and Administration (2.3)]. The mean duration of clinically useful contrast enhancement was approximately 2.7 minutes after bolus dose of microL/kg and 3.9 minutes after bolus dose of microL/kg.. Pulmonary Hemodynamic EffectsThe impact of DEFINITY on pulmonary hemodynamics was explored in 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.

DESCRIPTION SECTION.

11DESCRIPTION. DEFINITY RT (perflutren lipid microsphere) injectable suspension is, after activation, an ultrasound contrast agent for intravenous use.The perflutren lipid microspheres are composed of perflutren 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]- -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).Perflutren is chemically characterized as 1,1,1,2,2,3,3,3-octafluoropropane. It has molecular weight of 188, empirical formula of C3F8 and has the following structural formula:DPPA has molecular weight of 670, empirical formula of C35H68O8PNa, and following structural formula:DPPC has 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 Mg2+ and the following structural formula:Prior to activation, perflutren is in the headspace of the vial with concentration of 6.52 mg/mL which is confirmed by positive IR spectroscopic testing in every vial. The lipid blend is in the clear, colorless to translucent (hazy), viscous sterile solution. Each mL of the solution contains 3.75 mg lipid blend (consisting of 0.225 mg DPPA, 2.005 mg DPPC, and 1.520 mg MPEG5000 DPPE) and the following inactive ingredients: 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 activation with the aid of VIALMIX RFID and dilution with 1.4 mL of preservative-free 0.9% Sodium Chloride, Injection, USP, each mL of the activated DEFINITY RT as homogeneous 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, maximum of 1.2 1010 perflutren lipid microspheres, and about 80 microL/mL (0.65 mg/mL) perflutren. The microsphere particle size parameters are listed in Table below:Table 2Microsphere Size DistributionMicrosphere particle size parametersMean diameter range1.1 um 3.3 umPercent less than 10 um98%Maximum diameter20 um. Chemical Structure. Chemical Structure. Chemical Structure. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adult PatientsBolus: 10 microL/kg intravenously over 30 seconds to 60 seconds followed by 10 mL flush of 0.9% Sodium Chloride Injection.Infusion: 1.3 mL added to 50 mL of 0.9% Sodium Chloride Injection intravenously starting at mL/minute, titrating as necessary, not to exceed 10 mL/minutes.The maximum dose is two bolus doses 30 minute apart or one single infusion. (2.2) Pediatric PatientsBolus: microL/kg over 30 seconds to 60 seconds by intravenous bolus injection followed by 5 mL flush of 0.9% Sodium Chloride Injection.The maximum dose is two bolus doses 30 minute apart. (2.3) See Full Prescribing Information for imaging instructions and preparation (2.4, 2.5).. Adult PatientsBolus: 10 microL/kg intravenously over 30 seconds to 60 seconds followed by 10 mL flush of 0.9% Sodium Chloride Injection.Infusion: 1.3 mL added to 50 mL of 0.9% Sodium Chloride Injection intravenously starting at mL/minute, titrating as necessary, not to exceed 10 mL/minutes.The maximum dose is two bolus doses 30 minute apart or one single infusion. (2.2) Bolus: 10 microL/kg intravenously over 30 seconds to 60 seconds followed by 10 mL flush of 0.9% Sodium Chloride Injection.. Infusion: 1.3 mL added to 50 mL of 0.9% Sodium Chloride Injection intravenously starting at mL/minute, titrating as necessary, not to exceed 10 mL/minutes.. The maximum dose is two bolus doses 30 minute apart or one single infusion. (2.2). Pediatric PatientsBolus: microL/kg over 30 seconds to 60 seconds by intravenous bolus injection followed by 5 mL flush of 0.9% Sodium Chloride Injection.The maximum dose is two bolus doses 30 minute apart. (2.3) Bolus: microL/kg over 30 seconds to 60 seconds by intravenous bolus injection followed by 5 mL flush of 0.9% Sodium Chloride Injection.. The maximum dose is two bolus doses 30 minute apart. (2.3). See Full Prescribing Information for imaging instructions and preparation (2.4, 2.5).. 2.1Important Preparation and Administration Instructions. There are two formulations, DEFINITY and DEFINITY RT, that have differences in preparation and storage. Ensure of the correct product when following the directions for preparation and storage.DEFINITY RT must be activated using the VIALMIX RFID device and diluted before administration according to the instructions outlined below [see Dosage and Administration (2.5)].DEFINITY RT is for intravenous use only and must not be administered by intra-arterial injection [see Warnings and Precautions (5.3)].For adult patients, DEFINITY RT can be administered by either an intravenous bolus or infusion. The maximum dose is either two bolus doses or one single infusion. Do not administer the bolus and infusion dosing in combination or in sequence [see Dosage and Administration (2.2)].For pediatric patients, DEFINITY RT is administered by an intravenous bolus injection only. The maximum dose is two bolus doses [see Dosage and Administration (2.3)]. There are two formulations, DEFINITY and DEFINITY RT, that have differences in preparation and storage. Ensure of the correct product when following the directions for preparation and storage.. DEFINITY RT must be activated using the VIALMIX RFID device and diluted before administration according to the instructions outlined below [see Dosage and Administration (2.5)].. DEFINITY RT is for intravenous use only and must not be administered by intra-arterial injection [see Warnings and Precautions (5.3)].. For adult patients, DEFINITY RT can be administered by either an intravenous bolus or infusion. The maximum dose is either two bolus doses or one single infusion. Do not administer the bolus and infusion dosing in combination or in sequence [see Dosage and Administration (2.2)].. For pediatric patients, DEFINITY RT is administered by an intravenous bolus injection only. The maximum dose is two bolus doses [see Dosage and Administration (2.3)]. 2.2Recommended Dosage in Adult Patients. Bolus DosingThe recommended bolus dose in adult patients is 10 microL/kg of activated DEFINITY RT administered intravenously over 30 seconds to 60 seconds followed by 10 mL flush of 0.9% Sodium Chloride Injection, USP. If necessary, administer second 10 microL/kg dose followed by second 10 mL flush of 0.9% Sodium Chloride Injection, USP 30 minutes after the first injection to prolong contrast enhancement.. Infusion DosingThe recommended infusion dose in adult patients is 1.3 mL of activated DEFINITY RT added to 50 mL of preservative-free 0.9% Sodium Chloride Injection, USP administered intravenously. Initiate infusion at mL/minute, titrating the infusion rate as necessary to achieve optimal image enhancement, not to exceed 10 mL/minute.. 2.3Recommended Dosage in Pediatric Patients. Bolus DosingThe recommended bolus dose in pediatric patients is microL/kg of activated DEFINITY RT administered intravenously over 30 seconds to 60 seconds followed by 5 mL flush of 0.9% Sodium Chloride Injection, USP. If necessary, administer second bolus at dose of microL/kg to microL/kg, followed by second mL flush of 0.9% Sodium Chloride Injection, USP 30 minutes after the first injection to prolong contrast enhancement.. 2.4Imaging Instructions. Adult PatientsAfter 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 [see Clinical Pharmacology(12.2) Evaluate the DEFINITY RT echocardiogram images in combination with the non-contrast echocardiogram images.. Pediatric PatientsAfter baseline non-contrast echocardiography is completed, set the mechanical index for the ultrasound transducer at 0.3 or below [see Warnings and Precautions (5.4)]. Then inject activated DEFINITY RT (as described above) and begin ultrasound imaging immediately [see Clinical Pharmacology(12.2) Evaluate the DEFINITY RT echocardiogram images in combination with the non-contrast echocardiogram images.. 2.5Instructions for Activation, Preparation, and Handling of Definity RT. Adhere to strict aseptic procedures during preparation.Activate DEFINITY RT by shaking the vial for 45 seconds using VIALMIX RFID device.Note: Use only the drug activated in properly functioning VIALMIX RFID for full 45 second activation cycle. Do not reactivate the vial if VIALMIX RFID did not properly activate the vial. Never reactivate successfully activated DEFINITY RT vial (see step 3).Refer to the VIALMIX RFID Users Guide for illustrations of the activation procedure and properly functioning VIALMIX RFIDImmediately after activation, but no more than 15 minutes, place the activated DEFINITY RT vial in the upright position and remove the flip top cap. Insert the 13mm ViaLok (Vented Vial Access Device) into the center of the rubber stopper and push down until properly engaged and locked onto the vial.Attach 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 homogenous milky white suspension with presence of foam/bubbles. Use the product within minutes of dilution. If not used within minutes resuspend the microspheres by rapidly swirling the upright vial for 10 seconds before the product is withdrawn in syringe.The activated DEFINITY RT may be used for up to 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. Store the activated, diluted DEFINITY RT at room temperature 20 to 25C (68 to 77F) in the original product vial with the 13mm ViaLok still attached. sterile syringe or cap should be attached to the Luer fitting on the ViaLok until use.Invert the vial and withdraw the activated homogeneous 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 infusion dosing in adult patients, dilute 1.3 mL of activated, diluted Definity RT further in 50 mL of preservative-free 0.9% Sodium Chloride Injection, USP.Parenteral drug products should be inspected visually for foreign particulate matter and discoloration prior to administration, whenever solution and container permit. Adhere to strict aseptic procedures during preparation.. Activate DEFINITY RT by shaking the vial for 45 seconds using VIALMIX RFID device.Note: Use only the drug activated in properly functioning VIALMIX RFID for full 45 second activation cycle. Do not reactivate the vial if VIALMIX RFID did not properly activate the vial. Never reactivate successfully activated DEFINITY RT vial (see step 3).Refer to the VIALMIX RFID Users Guide for illustrations of the activation procedure and properly functioning VIALMIX RFID. Immediately after activation, but no more than 15 minutes, place the activated DEFINITY RT vial in the upright position and remove the flip top cap. Insert the 13mm ViaLok (Vented Vial Access Device) into the center of the rubber stopper and push down until properly engaged and locked onto the vial.. Attach 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 homogenous milky white suspension with presence of foam/bubbles. Use the product within minutes of dilution. If not used within minutes resuspend the microspheres by rapidly swirling the upright vial for 10 seconds before the product is withdrawn in syringe.. The activated DEFINITY RT may be used for up to 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. Store the activated, diluted DEFINITY RT at room temperature 20 to 25C (68 to 77F) in the original product vial with the 13mm ViaLok still attached. sterile syringe or cap should be attached to the Luer fitting on the ViaLok until use.. Invert the vial and withdraw the activated homogeneous 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 infusion dosing in adult patients, dilute 1.3 mL of activated, diluted Definity RT further in 50 mL of preservative-free 0.9% Sodium Chloride Injection, USP.. Parenteral drug products should be inspected visually for foreign particulate matter and discoloration prior to administration, whenever solution and container permit. 2.6Instructions for RFID-Tagged Vials. The radio frequency identification (RFID) tag integrated on the back of the vial label when used with VIALMIX RFID allows for the exchange of product information such as activation time and activation rate. If the RFID tag is damaged or otherwise non-functional, the vial with the non-functional RFID tag cannot be activated with VIALMIX RFID. Discard the non-functional RFID-tagged vial. Do not activate RFID-tagged DEFINITY RT vials in the VIALMIX RFID within inches (15 cm) of pacemaker and/or defibrillator (see the VIALMIX RFID Users Guide).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. DEFINITY RT is supplied in single-patient use vial containing 6.52 mg/mL perflutren in the headspace and 3.75 mg/mL of lipid blend as clear colorless to translucent viscous solution with 0.35 mL volume. After activation and dilution each mL contains maximum of 1.2 1010 perflutren lipid microspheres as homogeneous milky white injectable suspension, and about 80 microL/mL (0.65 mg/mL) perflutren.. DEFINITY RT: 6.52 mg/mL perflutren in the head space and 3.75 mg/mL of lipid blend as viscous solution with 0.35 mL volume in single-patient use vial; after activation and dilution, each mL contains maximum of 1.2 1010 perflutren lipid microspheres as injectable suspension. (3).

GERIATRIC USE SECTION.

8.5Geriatric Use. 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 between the elderly and younger patients.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedDEFINITY RT (perflutren lipid microsphere) injectable suspension is supplied in single-patient use clear glass Radio Frequency Identification (RFID)-tagged vial containing 6.52 mg/mL perflutren in the headspace of the vial and 3.75 mg/mL of lipid blend in colorless, uniformly clear to translucent (hazy) viscous solution phase with 0.35 mL volume. DEFINITY RT is available in the following packages:One (1) RFID-tagged vial per carton NDC (11994-017-01)Twenty (20) RFID-tagged vials per carton NDC (11994-017-20)Order VIALMIX RFID from Lantheus Medical Imaging. One (1) RFID-tagged vial per carton NDC (11994-017-01). Twenty (20) RFID-tagged vials per carton NDC (11994-017-20). Storage and HandlingStore at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DEFINITY RT is indicated, after activation, 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 endocardial border.. DEFINITY RT is an ultrasound contrast agent indicated, after activation, 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 endocardial border. (1).

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Hypersensitivity ReactionsAdvise patients to inform their healthcare provider if they develop any symptoms of hypersensitivity after DEFINITY RT administration, including rash, wheezing, or shortness of breath [see Warnings and Precautions (5.2)].

LACTATION SECTION.

8.2Lactation. Risk SummaryThere are no data on the presence of perflutren lipid microspheres in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DEFINITY RT and any potential adverse effects on the breastfed infant from DEFINITY RT or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1Mechanism 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 mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below mechanical index of 0.8.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, and Impairment of Fertility. Studies with activated DEFINITY RT 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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 2 mL Vial Carton. DEFINITY(R) RT (Perflutren Lipid Microsphere) INJECTABLE SUSPENSIONNDC 11994-017-20 STERILE20x2 mL vialsNon-PyrogenicFor Intravenous Use Only Must Activate and Dilute with 1.4 mL of0.9% Sodium Chloride Injection, USP Prior to UseUse the 13mm ViaLok(R) (Vented Vial Access Device) (packaged separately) during dilution and withdrawal of DEFINITY(R) RTStore at Room Temperature 20 to 25C (68 to 77F)Single Patient Use. Discard Unused Portion.CONTAINS NO BACTERIOSTATIC PRESERVATIVELantheus Medical Imaging(R) Rx Only. PRINCIPAL DISPLAY PANEL 2 mL Vial Carton.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of perflutren gas was evaluated in healthy subjects (n=8) after the intravenous administration of activated DEFINITY at 50 microL/kg (5 times the recommended dose).. DistributionPerflutren 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 its low partition coefficient into whole blood.. Elimination. MetabolismPerflutren is stable gas that is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids.. ExcretionPerflutren was not detectable after 10 minutes in most subjects either in the blood or in expired air. Perflutren concentrations in blood were shown to decline in mono-exponential fashion with mean half-life of 1.3 minutes in healthy subjects.. Specific Populations. Patients with Obstructive Pulmonary DiseaseThe pharmacokinetics of perflutren gas was evaluated in subjects (n=11) with chronic obstructive pulmonary disease (COPD). The mean half-life of perflutren in blood was 1.9 minutes. The total lung clearance of perflutren was similar to that in healthy subjects.

POSTMARKETING EXPERIENCE SECTION.

6.2Postmarketing Experience. Adverse Reactions from Observational StudiesIn prospective, multicenter, open-label registry of 1,053 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.. Adverse Reactions from Postmarketing Spontaneous ReportsThe 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. CardiopulmonaryFatal 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.. Immune SystemAnaphylaxis, 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.. NeurologicComa, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue.. Blood and Lymphatic SystemAcute pain episodes including vaso-occlusive crisis in patients with sickle cell disease.

PREGNANCY SECTION.

8.1Pregnancy. Risk SummaryAvailable data from case reports with DEFINITY RT use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DEFINITY RT has very short half-life; therefore, administration of DEFINITY RT to pregnant woman is not expected to result in clinically relevant fetal exposure. No adverse developmental outcomes were observed in animal reproduction studies with administration of activated DEFINITY, another formulation of perflutren lipid microspheres, in pregnant rats and rabbits during organogenesis at doses up to and 16 times, respectively, the maximum human dose based on body surface area (see Data).All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataDEFINITY was administered intravenously to rats at doses of 0.1mL/kg, 0.3 mL/kg, and mL/kg (approximately 0.8, 2.4, and times the recommended maximum human dose based on body surface area); DEFINITY doses were administered daily from day to day 17 of gestation. DEFINITY was administered intravenously to rabbits at doses of 0.1mL/kg, 0.3 mL/kg, and mL/kg (approximately, 1.6, 4.8, and 16 times the recommended maximum human dose based on body surface area); DEFINITY doses were administered daily from day to day 19 of gestation. No significant findings on the fetus were observed.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)3/2024Dosage and Administration (2.1,2.3,2.4)3/2024Warnings and Precautions, Pain Episodes in Patients with Sickle Cell Disease (5.5)6/2023.

SPL UNCLASSIFIED SECTION.

2.1Important Preparation and Administration Instructions. There are two formulations, DEFINITY and DEFINITY RT, that have differences in preparation and storage. Ensure of the correct product when following the directions for preparation and storage.DEFINITY RT must be activated using the VIALMIX RFID device and diluted before administration according to the instructions outlined below [see Dosage and Administration (2.5)].DEFINITY RT is for intravenous use only and must not be administered by intra-arterial injection [see Warnings and Precautions (5.3)].For adult patients, DEFINITY RT can be administered by either an intravenous bolus or infusion. The maximum dose is either two bolus doses or one single infusion. Do not administer the bolus and infusion dosing in combination or in sequence [see Dosage and Administration (2.2)].For pediatric patients, DEFINITY RT is administered by an intravenous bolus injection only. The maximum dose is two bolus doses [see Dosage and Administration (2.3)]. There are two formulations, DEFINITY and DEFINITY RT, that have differences in preparation and storage. Ensure of the correct product when following the directions for preparation and storage.. DEFINITY RT must be activated using the VIALMIX RFID device and diluted before administration according to the instructions outlined below [see Dosage and Administration (2.5)].. DEFINITY RT is for intravenous use only and must not be administered by intra-arterial injection [see Warnings and Precautions (5.3)].. For adult patients, DEFINITY RT can be administered by either an intravenous bolus or infusion. The maximum dose is either two bolus doses or one single infusion. Do not administer the bolus and infusion dosing in combination or in sequence [see Dosage and Administration (2.2)].. For pediatric patients, DEFINITY RT is administered by an intravenous bolus injection only. The maximum dose is two bolus doses [see Dosage and Administration (2.3)].

STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1Pregnancy. Risk SummaryAvailable data from case reports with DEFINITY RT use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DEFINITY RT has very short half-life; therefore, administration of DEFINITY RT to pregnant woman is not expected to result in clinically relevant fetal exposure. No adverse developmental outcomes were observed in animal reproduction studies with administration of activated DEFINITY, another formulation of perflutren lipid microspheres, in pregnant rats and rabbits during organogenesis at doses up to and 16 times, respectively, the maximum human dose based on body surface area (see Data).All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataDEFINITY was administered intravenously to rats at doses of 0.1mL/kg, 0.3 mL/kg, and mL/kg (approximately 0.8, 2.4, and times the recommended maximum human dose based on body surface area); DEFINITY doses were administered daily from day to day 17 of gestation. DEFINITY was administered intravenously to rabbits at doses of 0.1mL/kg, 0.3 mL/kg, and mL/kg (approximately, 1.6, 4.8, and 16 times the recommended maximum human dose based on body surface area); DEFINITY doses were administered daily from day to day 19 of gestation. No significant findings on the fetus were observed.. 8.2Lactation. Risk SummaryThere are no data on the presence of perflutren lipid microspheres in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DEFINITY RT and any potential adverse effects on the breastfed infant from DEFINITY RT or from the underlying maternal condition.. 8.4Pediatric Use. The safety and effectiveness of DEFINITY RT have been established for use in pediatric patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve delineation of the left endocardial border. Use of DEFINITY RT for this indication is supported by evidence from adequate and well-controlled studies in adults [see Clinical Studies (14)], pharmacodynamic and safety study in 40 pediatric patients month of age and older [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2)], and published studies in 149 patients years to 24 years of age [see Adverse Reactions (6.1)].. 8.5Geriatric Use. 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 between the elderly and younger patients.