Definity

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) ] 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. 6.1 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. Serious Adverse Reactions Among the 1716 study patients, 19 (1.1%) suffered serious cardiopulmonary adverse reactions. For all adverse reactions, the overall incidence of adverse experiences was similar for the <65 year age group and the > 65 year age group, similar in males and in females, similar among all racial or ethnic groups, and similar for bolus and infusion dosing. Table 1 summarizes the most common adverse reactions. Table 1 New-Onset Adverse Reactions Occurring in ≥0.5% of All DEFINITY-Treated Subjects DEFINITY (N=1716) N=Sample size 1716 subjects who received activated DEFINITY n=Number of subjects reporting at least one Adverse Reaction Total Number of Adverse Reactions 269 Total Number of Subjects with an Adverse Reaction 144 (8.4%) Body system Preferred term n (%) Application Site Disorders 11 (0.6) Injection Site Reactions 11 (0.6) Body as a Whole 41 (2.4) Back/renal pain 20 (1.2) Chest pain 13 (0.8) Central and peripheral nervous system disorder 54 (3.1) Headache 40 (2.3) Dizziness 11 (0.6) Gastrointestinal system 31 (1.8) Nausea 17 (1.0) Vascular (extracardiac) disorders 19 (1.1) Flushing 19 (1.1) Other adverse reactions that occurred in ≤0.5% of the activated DEFINITY-dosed subjects were: Body as a Whole: Fatigue, fever, hot flushes, pain, rigors, and syncope Cardiovascular: Abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension and hypotension Digestive: Dyspepsia, dry mouth, tongue disorder, toothache, abdominal pain, diarrhea and vomiting Hematology: Granulocytosis, leukocytosis, leukopenia, and eosinophilia Musculoskeletal: Arthralgia Nervous System: Leg cramps, hypertonia, vertigo and paresthesia Platelet, Bleeding, and Clotting: Hematoma Respiratory: Coughing, hypoxia, pharyngitis, rhinitis and dyspnea Special Senses: Decreased hearing, conjunctivitis, abnormal vision and taste perversion Skin: Pruritus, rash, erythematous rash, urticaria, increased sweating, and dry skin Urinary: Albuminuria 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: Cardiopulmonary 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. Hypersensitivity 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. Neurologic Coma, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue. Blood and Lymphatic System Acute pain episodes including vaso-occlusive crisis in patients with sickle cell disease

4 CONTRAINDICATIONS Do not administer DEFINITY 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) ] . Do not administer DEFINITY to patients with known or suspected: Hypersensitivity to perflutren lipid microsphere or its components, such as polyethylene glycol (PEG). ( 4 )

11 DESCRIPTION DEFINITY ( Perflutren Lipid Microsphere ) Injectable Suspension is an ultrasound contrast agent. The DEFINITY vial contains components that upon activation yield perflutren lipid microspheres. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic liquid, which upon activation with the aid of a VIALMIX or VIALMIX RFID, provides a homogeneous, opaque, milky white injectable suspension of perflutren lipid microspheres. The suspension of activated DEFINITY 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-( m ethoxy p oly e thylene g lycol 5000 carbamoyl)-1,2- d i p almitoyl-sn-glycero-3- p hosphatidyl e thanolamine, 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 C 3 F 8 and has the following structural formula: DPPA has a molecular weight of 670, empirical formula of C 35 H 68 O 8 PNa, and following structural formula: DPPC has a molecular weight of 734, empirical formula of C 40 H 80 NO 8 P, and following structural formula: MPEG5000 DPPE has an approximate molecular weight of 5750 represented by empirical formula C 265 H 527 NO 123 PNa, contains <100ppm Ca+2 and Mg+2 and the following structural formula: Prior to activation, the DEFINITY vial contains 6.52 mg/mL octafluoropropane in the headspace which was required to be confirmed by positive IR spectroscopic testing in every vial. Each mL of the clear liquid contains 0.75 mg lipid blend (consisting of 0.045 mg DPPA, 0.401 mg DPPC, and 0.304 mg MPEG5000 DPPE), 103.5 mg propylene glycol, 126.2 mg glycerin, 2.34 mg sodium phosphate monobasic monohydrate, 2.16 mg sodium phosphate dibasic heptahydrate, and 4.87 mg sodium chloride in Water for Injection. The pH is 6.2-6.8. DEFINITY does not contain bacterial preservative. After activating the contents of the DEFINITY vial, each mL of the milky white suspension contains a maximum of 1.2 × 10 10 perflutren lipid microspheres, and about 150 microL/mL (1.1 mg/mL) octafluoropropane. The microsphere particle size parameters are listed in Table 2 below: Table 2 Microsphere Size Distribution Microsphere particle size parameters Mean diameter range 1.1 µm – 3.3 µm Percent less than 10 µm 98% Maximum diameter 20 µm Chemical Structure Chemical Structure Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION DEFINITY may be injected by either an intravenous (IV) 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 is 10 microliters (microL)/kg of the activated product by intravenous bolus injection within 30 to 60 seconds, followed by a 10 mL saline flush. If necessary, a second 10 microliters (microL)/kg dose followed by a second 10 mL saline flush may be administered 30 minutes after the first injection to prolong contrast enhancement. ( 2.2 ) The recommended infusion dose for activated DEFINITY is via an IV infusion of 1.3 mL added to 50 mL of preservative-free saline. 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 ) 2.1 Important Administration Instructions DEFINITY is intended for administration only after activation in the VIALMIX or VIALMIX RFID apparatus. Before injection, this product must be activated and prepared according to the instructions outlined below. The VIALMIX or 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. DEFINITY may be injected by either an intravenous (IV) bolus or infusion. Do not administer DEFINITY 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. 2.2 Dosage Bolus The recommended bolus dose for activated DEFINITY is 10 microliters (microL)/kg of the activated product by intravenous bolus injection within 30 to 60 seconds, followed by a 10 mL saline flush. If necessary, a second 10 microliters (microL)/kg dose followed by a second 10 mL saline flush may be administered 30 minutes after the first injection to prolong contrast enhancement. Infusion The recommended infusion dose for activated DEFINITY is via an IV infusion of 1.3 mL added to 50 mL of preservative-free saline. 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. 2.3 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 (as described above) and begin ultrasound imaging immediately. Evaluate the activated DEFINITY echocardiogram images in combination with the non-contrast echocardiogram images. In a crossover trial of 64 patients randomized to both bolus and infusion, 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 saline at a rate of 4 mL/min. 2.4 DEFINITY Activation, Preparation and Handling Instructions Follow directions for activation of DEFINITY carefully and adhere to strict aseptic procedures during preparation. Allow the vial to warm to room temperature before starting the activation procedure. Activate DEFINITY by shaking the vial for 45 seconds using a VIALMIX device or VIALMIX RFID device. Note: illustrations of this procedure are contained in the VIALMIX or VIALMIX RFID User's Guide. Do not use this drug unless it has completed a full 45 second activation cycle in the VIALMIX or VIALMIX RFID. DEFINITY 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 or VIALMIX RFID did not properly activate the vial. Never reactivate a successfully activated DEFINITY vial (see step 3). A VIALMIX or VIALMIX RFID that is not functioning properly must never be used. Only use a vial activated from a properly functioning VIALMIX or VIALMIX RFID. Refer to the VIALMIX or VIALMIX RFID User's Guide to ensure that a properly functioning VIALMIX or VIALMIX RFID is used. Immediately after activation in the VIALMIX or VIALMIX RFID, activated DEFINITY appears as a milky white suspension and may be used immediately after activation. If the product is not used within 5 minutes of activation, the microspheres should be resuspended by 10 seconds of hand agitation by inverting the vial before the product is withdrawn in a syringe. The activated DEFINITY may be used for up to 12 hours from the time of activation, but only after the microspheres are resuspended by hand agitation. Store the activated DEFINITY at room temperature in the original product vial. Invert the vial and withdraw the activated milky white suspension using the Intellipin (Dispensing Pin), the PINSYNC (Vented Vial Adapter 13mm), or 18 to 20 gauge syringe needle. Withdraw the material from the middle of the liquid in the inverted vial. Do not inject air into the DEFINITY Vial. Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe. Special Instructions for the DEFINITY Radio Frequency Identification (RFID)-Tagged Vial This information is for vials containing DEFINITY that have been labeled with a Radio Frequency Identification (RFID) tag. Full instructions for use of VIALMIX RFID are provided on the VIALMIX RFID screen and User's Guide. The RFID tag allows for the exchange of product information such as activation time and activation rate. VIALMIX RFID will only activate DEFINITY RFID-tagged vials. Function of the RFID technology is not dependent on vial orientation as it is placed in the VIALMIX RFID. If the RFID tag is damaged or otherwise non-functional, the VIALMIX RFID will notify the user and the vial with the nonfunctional RFID tag cannot be used to activate DEFINITY with VIALMIX RFID. Discard the nonfunctional RFID-tagged DEFINITY vial. Follow all manufacturers' guidelines and do not operate any part of the VIALMIX RFID with DEFINITY RFID-tagged vials within 6 inches (15 cm) of a pacemaker and/or defibrillator.

1 INDICATIONS AND USAGE Activated DEFINITY (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. DEFINITY 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.

12 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 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. 12.3 Pharmacokinetics Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of octafluoropropane gas (OFP) was evaluated in healthy subjects (n=8) after the IV administration of activated DEFINITY at a 50 microL/kg dose. Distribution OFP gas binding to plasma proteins or partitioning into blood cells has not been studied. However, OFP protein binding is expected to be minimal due to its low partition coefficient into whole blood. Metabolism OFP is a stable gas that is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids. Elimination OFP was not detectable after 10 minutes in most subjects either in the blood or in expired air. OFP concentrations in blood were shown to decline in a mono-exponential fashion with a mean half-life of 1.3 minutes in healthy subjects. Special Populations The pharmacokinetics of octafluoropropane gas (OFP) was evaluated in subjects (n=11) with chronic obstructive pulmonary disease (COPD). The mean half-life of OFP in blood was 1.9 minutes. The total lung clearance of OFP was similar to that in healthy subjects. The pharmacokinetics of activated DEFINITY has not been studied in subjects with hepatic diseases or congestive heart failure.

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 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.

12.3 Pharmacokinetics Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of octafluoropropane gas (OFP) was evaluated in healthy subjects (n=8) after the IV administration of activated DEFINITY at a 50 microL/kg dose. Distribution OFP gas binding to plasma proteins or partitioning into blood cells has not been studied. However, OFP protein binding is expected to be minimal due to its low partition coefficient into whole blood. Metabolism OFP is a stable gas that is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids. Elimination OFP was not detectable after 10 minutes in most subjects either in the blood or in expired air. OFP concentrations in blood were shown to decline in a mono-exponential fashion with a mean half-life of 1.3 minutes in healthy subjects. Special Populations The pharmacokinetics of octafluoropropane gas (OFP) was evaluated in subjects (n=11) with chronic obstructive pulmonary disease (COPD). The mean half-life of OFP in blood was 1.9 minutes. The total lung clearance of OFP was similar to that in healthy subjects. The pharmacokinetics of activated DEFINITY has not been studied in subjects with hepatic diseases or congestive heart failure.

20230818

30

3 DOSAGE FORMS AND STRENGTHS DEFINITY is supplied as a single patient use 2 mL clear glass vial or RFID-tagged vial containing a clear liquid in packages of four (4) and sixteen (16) single patient use vials. Prior to activation, the headspace of each vial contains 6.52 mg/mL octafluoropropane and the clear liquid contains 0.75mg/mL of a lipid blend. After activation, each vial contains a maximum of 1.2 × 10 10 perflutren lipid microspheres, and about 150 microL/mL (1.1 mg/mL) octafluoropropane [see Description (11) ] . DEFINITY is supplied as a single patient use 2 mL clear glass vial or RFID-tagged vial containing clear liquid in packages of four (4) and sixteen (16) single patient use vials.

Definity perflutren PERFLUTREN PERFLUTREN PROPYLENE GLYCOL GLYCERIN SODIUM CHLORIDE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE

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).

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).

NDA021064

Definity

perflutren

11994-011

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 2 mL Vial Carton DEFINITY® VIAL FOR (Perflutren Lipid Microsphere) INJECTABLE SUSPENSION NDC 11994-011-16 Sterile CAUTION: Rx Only 16x2 mL Single-Dose Containers Non-Pyrogenic For Intravenous Use Only, After Activation Store refrigerated, 2–8° C (36–46° F) For Single Use Only, Discard Unused Portion Use within 12 hours of activation (see Insert) IMPORTANT: Read enclosed Package Insert for full information on preparation, use and indications. CONTAINS NO BACTERIOSTATIC PRESERVATIVE Lantheus Medical Imaging PRINCIPAL DISPLAY PANEL - 2 mL Vial Carton

Warnings and Precautions, Pain Episodes in Patients with Sickle Cell Disease ( 5.5 ) 6/2023

Distributed By Lantheus Medical Imaging 331 Treble Cove Road N. Billerica, Massachusetts 01862 USA For ordering, call toll free: 800-299-3431 All Other Business: 800-362-2668 (For Massachusetts and International, call 978-667-9531) Patent: http://www.lantheus.com/patents/index.html 515987-0222

17 PATIENT COUNSELING INFORMATION Advise patients to inform their healthcare provider if they develop any symptoms of hypersensitivity after DEFINITY administration, including rash, wheezing, or shortness of breath.

14 CLINICAL STUDIES 14.1 Echocardiography A total of 249 subjects were evaluated in clinical trials (208 received activated DEFINITY and 41 placebo). In this group, 154 (61.8%) were male and 95 (38.2%) were female; 183 (73.5%) were White, 38 (15.3%) were Black, 21 (8.4%) were Hispanic, and 7 (2.8%) were classified as other racial or ethnic groups. The mean age was 53.9 years (range 18 to 87). Activated DEFINITY was evaluated in four controlled clinical trials: Two open-label baseline controlled, unpaired blinded image evaluation studies and two identical placebo-controlled, unpaired blinded image evaluation studies. Subjects were eligible for these studies if they had two or more (of six) non-evaluable segments in either the apical 2- or 4-chamber view in non-contrast fundamental echocardiography. In the baseline controlled studies, a total of 126 (67 in study A and 59 in study B) subjects received a 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 a total of 123 subjects were randomized in 1:2 ratio to receive two IV bolus doses of either saline (placebo) or activated DEFINITY 10 microL/kg (17 placebo vs. 33 activated DEFINITY patients and 24 placebo vs. 49 activated DEFINITY patients, respectively). The outcome measure for assessing the effectiveness of activated DEFINITY was the blinded assessment of improvement in ventricular chamber enhancement (measured by videodensitometry at end-diastole and end-systole). Endocardial Border Length As shown in Table 3, compared to baseline, a 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 3 out of 4 readers for the apical 2-chamber view. The mean change in border length from baseline at end-systole was statistically significant for 3 out of 4 readers for the apical 4-chamber view and for 2 out of 4 readers for the apical 2-chamber view. Ventricular Chamber Enhancement Left 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 Motion In a retrospective analysis, in a subset of subjects (n=12 to 47, depending on reader) having at least 2 adjacent segments non-evaluable on non-contrast imaging, activated DEFINITY converted a baseline non-evaluable image to an evaluable image in 58 to 91% of the patients, 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 patients, 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 patients, depending on the reader, activated DEFINITY was found to obscure the wall motion rendering the image non-evaluable. Ejection Fraction In the 2 baseline controlled studies, ejection fraction results were evaluated in comparison to MRI. The results were evaluated by 3 blinded, independent radiologists. In these studies, although there was a statistically significant increase in ventricular chamber enhancement, activated DEFINITY did not significantly improve the assessment of ejection fraction compared to the baseline images. Table 3 MEAN (SD) ENDOCARDIAL BORDER LENGTH (CM) BY BOTH APICAL 2- AND 4-CHAMBER VIEWS AT END-SYSTOLE AND END-DIASTOLE BY STUDY, EVALUABLE SUBJECTS Study/View Endocardial Border Length – Blinded Read Mean(SD) at End-Diastole Mean(SD) at End-Systole Reader 1 Reader 2 Reader 1 Reader 2 Activated DEFINITY Bolus Dose = 10 microL/kg Study A: (N = 67) Apical 2-chamber Baseline 8.0(3.4) 4.7(2.8) 7.1(3.3) 4.3(2.6) Post-DEFINITY 12.8(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 Baseline 8.1(3.3) 4.5(2.6) 7.6(3.2) 4.5(2.7) Post-DEFINITY 13.5(5.2) 6.8(3.3) 11.5(4.4) 5.3(3.1) Study B: (N = 59) Apical 2-chamber Baseline 4.3(2.6) 7.8(5.3) 4.1(2.4) 6.5(5.1) Post-DEFINITY 5.7(4.7) 8.2(6.5) 5.5(4.4) 6.9(6.3) Apical 4-chamber Baseline 4.0(2.7) 9.2(5.9) 3.8(2.6) 7.3(5.6) Post-DEFINITY 7.1(5.5) 11.5(7.5) 5.9(5.3) 8.7(6.3) In an open administration, crossover trial, 64 patients were randomized to receive both bolus (10 microL/kg) and infusion (1.3 mL activated DEFINITY in 50 mL saline at the rate of 4 mL/min) dosing of activated DEFINITY. Outcome measures for this study included clinically useful ventricular cavity enhancement and endocardial border length. Similar results were seen as described above. Optimal activated DEFINITY doses and device settings for harmonic imaging have not been established. 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.

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.

8.4 Pediatric Use The safety and effectiveness of activated DEFINITY have not been established in the pediatric population. The safety of injecting activated DEFINITY in neonates and infants with immature pulmonary vasculature has not been studied. The pharmacokinetics of activated DEFINITY in pediatric subjects has not been studied.

8.1 Pregnancy Risk Summary Available data from case reports with DEFINITY use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DEFINITY has a very short half-life; therefore, administration of DEFINITY to a 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 in pregnant rats and rabbits during organogenesis at doses up to 8 and 16 times, respectively, the maximum human dose based on body surface area (see Data ) . All pregnancies have a 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 2-4% and 15-20%, respectively. Data Animal Data DEFINITY was administered intravenously to rats at doses of 0.1, 0.3, and 1.0 mL/kg (approximately 0.8, 2.4, and 8 times the recommended maximum human dose based on body surface area); DEFINITY doses were administered daily from day 6 to day 17 of gestation. DEFINITY was administered intravenously to rabbits at doses of 0.1, 0.3, and 1.0 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 7 to day 19 of gestation. No significant findings on the fetus were observed.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from case reports with DEFINITY use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DEFINITY has a very short half-life; therefore, administration of DEFINITY to a 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 in pregnant rats and rabbits during organogenesis at doses up to 8 and 16 times, respectively, the maximum human dose based on body surface area (see Data ) . All pregnancies have a 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 2-4% and 15-20%, respectively. Data Animal Data DEFINITY was administered intravenously to rats at doses of 0.1, 0.3, and 1.0 mL/kg (approximately 0.8, 2.4, and 8 times the recommended maximum human dose based on body surface area); DEFINITY doses were administered daily from day 6 to day 17 of gestation. DEFINITY was administered intravenously to rabbits at doses of 0.1, 0.3, and 1.0 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 7 to day 19 of gestation. No significant findings on the fetus were observed. 8.2 Lactation Risk Summary There are no data on the presence of DEFINITY 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 mother's clinical need for DEFINITY and any potential adverse effects on the breastfed infant from DEFINITY or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of activated DEFINITY have not been established in the pediatric population. The safety of injecting activated DEFINITY in neonates and infants with immature pulmonary vasculature has not been studied. The pharmacokinetics of activated DEFINITY 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied DEFINITY is supplied as a single patient use 2 mL clear glass vial or a single patient use 2 mL clear glass Radio Frequency Identification (RFID)-tagged vial containing clear liquid in packages of four (4) and sixteen (16) single patient use vials. One (1) 2 mL vial or 2 mL RFID-tagged vial NDC (11994-011-01) Four (4) 2 mL vials or 2 mL RFID-tagged vials per kit - NDC (11994-011-04) Sixteen (16) 2 mL vials or 2 mL RFID-tagged vials per kit - NDC (11994-011-16) 16.2 Storage and Handling Store between 2° to 8°C (36° to 46°F). 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.

16.2 Storage and Handling Store between 2° to 8°C (36° to 46°F). 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.

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 administration [see Contraindications (4) ] . Always have resuscitation equipment and trained personnel readily available. 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 administration ( 4 ). Always have resuscitation equipment and trained personnel readily available.