Human Albumin Microspheres and Perflutren

OPTISON is indicated for use in adult and pediatric patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders. OPTISON is an ultrasound contrast agent indicated for use in adult and pediatric patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders ( 1 ).

Injectable suspension: 5-8×10 8 /mL protein-type A microspheres, 10 mg/mL albumin human, and 0.22 ± 0.11 mg/mL perflutren as a clear liquid lower layer, a white liquid upper layer, and a headspace filled with perflutren gas in 3 mL single-patient use vial; after resuspension, OPTISON is a sterile, homogeneous, opaque, and milky-white injectable suspension. Injectable suspension: 5-8 ×10 8 /mL protein-type A microspheres, 10 mg/mL albumin human, and 0.22 ± 0.11 mg/mL perflutren in 3 mL single-patient use vials ( 3 )

OPTISON is contraindicated in patients with known or suspected hypersensitivity to perflutren or albumin [see Warnings and Precautions (5.2) ] . Known or suspected hypersensitivity to perflutren or albumin ( 4 )

Hypersensitivity Reactions: Serious anaphylactic reactions have been observed. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to OPTISON administration and monitor all patients for hypersensitivity reactions ( 5.2 ).

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). The reported reactions to perflutren-containing microspheres 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) ] . Always have cardiopulmonary resuscitation personnel and equipment readily available prior to OPTISON administration and monitor all patients for acute reactions.

5.2 Hypersensitivity Reactions Serious anaphylactic reactions have been observed during or shortly following perflutren-containing microsphere administration including: shock, hypersensitivity, 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 have occurred in patients with no prior exposure to perflutren-containing microsphere products. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to OPTISON administration and monitor all patients for hypersensitivity reactions [see Adverse Reactions (6.2) ] .

5.3 Systemic Embolization When administering OPTISON to patients with a cardiac shunt, microspheres can bypass filtering of the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following OPTISON administration. OPTISON is only for intravenous administration; do not administer OPTISON by intra-arterial injection.

5.4 Ventricular Arrhythmia Related to High Mechanical Index High ultrasound mechanical index values may cause microsphere rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. OPTISON is not recommended for use at mechanical indices greater than 0.8.

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) ] Common adverse reactions (incidence ≥ 0.5%) were: headache, nausea and/or vomiting, warm sensation or flushing, dizziness, dysgeusia, chills or fever, flu-like symptoms, malaise/weakness/fatigue, chest pain, dyspnea, injection site discomfort, and erythema ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 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 The safety of OPTISON was evaluated in 279 adult patients in clinical studies. These patients were 69% male, 31% female, 71% White, 19% Black or African American, 9% Hispanic or Latino, and 1% other racial or ethnic groups. Adverse reactions reported in ≥ 0.5% of patients who received OPTISON by intravenous injection are given in Table 2. Table 2. Adverse Reactions Reported in ≥ 0.5% of the Adult Patients who Received OPTISON in Controlled Clinical Studies Adverse Reaction OPTISON n=279 % Body as a Whole Headache

5.4 Warm Sensation/Flushing

3.6 Chills/fever

1.4 Flu-like Symptoms

1.1 Malaise/Weakness/Fatigue

1.1 Cardiovascular System Dizziness

2.5 Chest Pain

1.1 Digestive System Nausea and/or Vomiting

4.3 Respiratory System Dyspnea

1.1 Skin & Appendages Injection Site Discomfort

1.1 Erythema

0.7 Special Senses Dysgeusia

1.8 Adverse reactions reported in < 0.5% of patients who received OPTISON included: Body as a Whole: induration, discoloration at the injection site Cardiovascular system : premature ventricular contractions, palpitations Digestive system : dry mouth Immune system disorders : hypersensitivity Musculoskeletal and connective tissue disorders : back pain, arthralgia, body or muscle aches Nervous system : tremor, paresthesia, irritableness Respiratory system : oxygen saturation decline due to coughing, wheezing Skin and appendages : urticaria, rash, pruritus Special Senses : tinnitus, visual blurring, photophobia, burning sensation in the eyes Adverse Reactions in Pediatric Patients Overall, the safety profile observed in pediatric patients from the clinical study was consistent with the safety profile in adult patients [see Clinical Studies (14.2) ].

6.2 Postmarketing Experience Adverse Reactions from Observational Studies In a prospective, post-marketing safety surveillance study of OPTISON used in routine clinical practice, a total of 1,039 patients received OPTISON. These patients had an average age of 59.9 years (min, max: 20, 97) and were 62% male, 38% female, 83% White, 14% Black or African American, 2% Asian, and 1.5% other racial or ethnic groups. Overall, 17% of patients reported at least one adverse event. No deaths or serious adverse reactions were reported in this study. Adverse Reactions from Postmarking Spontaneous Reports The following adverse reactions have been identified during the postmarketing use of OPTISON or other perflutren-containing microspheres. 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 or decreased oxygenation, 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, erythema. Neurologic Loss of consciousness, convulsion

8.1 Pregnancy Risk Summary There are no data with OPTISON use in pregnant women to inform any drug-associated risks. No adverse developmental outcomes were observed in animal reproduction studies with intravenous administration of OPTISON to pregnant rats and rabbits during organogenesis at doses up to at least 5 and 10 times the recommended human dose based on body surface area ( see Data ). 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 OPTISON was administered intravenously to rats at doses of 0.25, 5 and 10 mL/kg/day (approximately 0.2, 5, and 10 times the recommended maximum human dose of 8.7 mL, respectively, based on body surface area) and to rabbits at 0.25, 2.5, and 5 mL/kg/day (approximately 0.5, 5, and 10 times the recommended maximum human dose, respectively, based on body surface area) during organogenesis. No significant findings attributable solely to a direct effect on the fetus were detected in the studies.

8.2 Lactation There are no data on the presence of perflutren protein-type A 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 OPTISON and any potential adverse effects on the breastfed infant from OPTISON or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of OPTISON to opacify the left ventricle and improve the delineation of the left ventricular endocardial borders have been established in pediatric patients with suboptimal echocardiograms. Use of OPTISON in pediatric patients is supported by evidence from adequate and well-controlled studies in adults and additional efficacy and safety data from a clinical study in 37 pediatric patients aged 9 to 17 years old [see Adverse Reactions (6.1) and Clinical Studies (14.1 , 14.2) ].

8.5 Geriatric Use Of the total number of subjects in a clinical study of OPTISON, 35% were 65 and over, while 14% were 75 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.

The OPTISON microspheres create an echogenic contrast effect in the blood. The acoustic impedance of the OPTISON microspheres is much lower than that of the blood. Therefore, impinging ultrasound waves are scattered and reflected at the microsphere-blood interface and ultimately may be visualized in the ultrasound image. At the frequencies used in adult echocardiography (2 MHz to 5 MHz), the microspheres resonate which further increases the extent of ultrasound scattering and reflection.