Perflutren

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 )

DEFINITY RT is supplied in a single-patient use vial containing 6.52 mg/mL perflutren in the headspace and 3.75 mg/mL of a lipid blend as a clear colorless to translucent viscous solution with 0.35 mL volume. After activation and dilution each mL contains a maximum of 1.2 × 10 10 perflutren lipid microspheres as a 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 a lipid blend as viscous solution with 0.35 mL volume in a single-patient use vial; after activation and dilution, each mL contains a maximum of 1.2 × 10 10 perflutren lipid microspheres as injectable suspension. ( 3 )

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 )

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 )

5.1 Serious Cardiopulmonary Reactions Serious cardiopulmonary reactions including fatalities have occurred uncommonly during or shortly following perflutren-containing microsphere administration, typically within 30 minutes of administration. The risk for these reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias). Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY RT administration and monitor all patients for acute reactions. The reported reactions include: fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, and convulsions [see Adverse Reactions (6.2) ] .

5.2 Hypersensitivity Reactions In postmarketing use, serious hypersensitivity reactions were observed during or shortly following perflutren-containing microsphere administration including: Anaphylaxis, with manifestations that may include death, shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema. These reactions have occurred in patients with no prior exposure to perflutren-containing microsphere products. DEFINITY RT contains PEG. There may be increased risk of serious reactions including death in patients with prior hypersensitivity reaction(s) to PEG [see Adverse Reactions (6.2) and Description (11) ] . Clinically assess patients for prior hypersensitivity reactions to products containing PEG, such as certain colonoscopy bowel preparations and laxatives. 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.

5.3 Systemic Embolization When administering DEFINITY RT to patients with a cardiac shunt, the microspheres can bypass filtering by the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following DEFINITY RT administration. DEFINITY RT is only for intravenous administration and must not be administered by intra-arterial injection [see Dosage and Administration (2.1 , 2.2 , 2.3) ] .

5.4 Ventricular Arrhythmia Related to High Mechanical Index High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. 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) ] .

5.5 Pain 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 a patient with sickle cell disease experiences new or worsening pain, discontinue DEFINITY RT.

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. Adverse Reactions in Adults Safety of DEFINITY RT was evaluated in a 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 a total of 15 (0.9%) subjects receiving DEFINITY in the clinical trials included urticaria, pruritus, dizziness, chest pain, dyspnea, and back pain. Table 1 summarizes the most common adverse reactions occurring at ≥0.5%. Table 1 Adverse Reactions Occurring in ≥0.5% of All DEFINITY-Treated Subjects DEFINITY (N=1716) Total Number of Adverse Reactions 269 Total Number of Subjects with an Adverse Reaction 144 (8.4%) Body system Preferred term n (%) N=Sample size 1716 subjects who received activated DEFINITY n=Number of subjects reporting at least one Adverse Reaction 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 Adverse Reactions in Pediatric Patients In a study of DEFINITY in 40 pediatric patients 1 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 5 years to 24 years of age (mean age 16.8 years; 56% male) clinically indicated for echocardiography, no additional safety signals were observed.

6.2 Postmarketing Experience Adverse Reactions from Observational Studies In a 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 Reports 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. 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. Immune System 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

8.1 Pregnancy Risk Summary Available data from case reports with DEFINITY RT use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DEFINITY RT has a very short half-life; therefore, administration of DEFINITY RT 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, another formulation of perflutren lipid microspheres, 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% to 4% and 15% to 20%, respectively. Data Animal Data DEFINITY was administered intravenously to rats at doses of 0.1mL/kg, 0.3 mL/kg, and 1 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 0.1mL/kg, 0.3 mL/kg, and 1 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 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 mother's clinical need for DEFINITY RT and any potential adverse effects on the breastfed infant from DEFINITY RT or from the underlying maternal condition.

8.4 Pediatric 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) ] , a pharmacodynamic and safety study in 40 pediatric patients 1 month of age and older [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2) ] , and published studies in 149 patients 5 years to 24 years of age [see Adverse Reactions (6.1) ] .

8.5 Geriatric 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.

Perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. These physical acoustic properties of activated DEFINITY RT provide contrast enhancement of the left ventricular chamber and aid delineation of the left ventricular endocardial border during echocardiography. In animal models the acoustic properties of activated DEFINITY were established at or below a mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below a mechanical index of 0.8.