|Dosage Form||Package Information||Links|
|INJECTION, SOLUTION||5 VIAL, SINGLE-USE in 1 CARTON (0407-2707-03) > 3 mL in 1 VIAL, SINGLE-USE||Label Information|
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following perflutren-containing microsphere administration. Most serious reactions occur within 30 minutes of administration [see Warnings and Precautions (5.1)].
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following perflutren-containing microsphere administration. Most serious reactions occur within 30 minutes of administration (5.1).
Optison is an ultrasound contrast agent indicated for use in patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders. (1)
Recommended Dosage (2.1)
Administration Instructions (2.3)
Injectable suspension: 5.0-8.0×108 protein-type A microspheres, 10 mg albumin human, and 0.22 ± 0.11 mg, perflutren per mL in 3mL single-patient use vials (3).
Most common adverse reactions during treatment: headache, nausea and/or vomiting, warm sensation or flushing, and dizziness (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.
See 17 for PATIENT COUNSELING INFORMATION.
Injectable suspension: 3 mL single-patient use vial containing a clear liquid lower layer and a white liquid upper layer, and a headspace filled with perflutren gas. Each mL of Optison contains 5-8×108 protein-type A microspheres, 10 mg albumin human, and 0.22 ± 0.11 mg perflutren. The sterile suspension is homogeneous, opaque, and milky-white after resuspension.
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.
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.
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.
This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral disease. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral disease or CJD have ever been identified for albumin.
The following serious adverse reactions are described elsewhere in the labeling:
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.
Optison was administered in clinical studies in 279 patients. Of these patients there were 192 (68.8%) men and 87 (31.2%) women. The racial demographics were 199 (71.3%) Caucasian, 52 (18.6%) Black, 24 (8.6%) Hispanic, and 4 (1.4%) other racial or ethnic groups.
In these patients, 47 (16.8%) reported at least one adverse reaction. Of these one reaction was serious and required treatment with antihistamines for hypersensitivity manifestations of dizziness, nausea, flushing and temperature elevation. Deaths were not reported during the clinical studies.
Of the reported adverse reactions following the use of Optison the most frequently reported were headache (5.4%), nausea and/or vomiting (4.3%), warm sensation or flushing (3.6%), and dizziness (2.5%). The most common adverse reactions observed in clinical studies of Optison are given in Table 1.
|(1) Patients are counted separately within each body system.|
|(2) The body system is reported if the aggregate is â‰¥ 0.5%.|
|Details are not shown if the subsystem is not â‰¥ 0.5%.|
|No. of Patients Exposed to Optison||279|
|No. of Patients Reporting on Adverse Reactions||47||(16.8%)|
|Body as a Whole||38||(13.6%)|
|Nausea and/or Vomiting||12||(4.3%)|
|Skin & Appendages||11||(3.9%)|
|Injection Site Discomfort||3||(1.1%)|
Adverse reactions reported in < 0.5% of subjects who received Optison included: arthralgia, back pain, body or muscle aches, induration, urticaria, dry mouth, palpitations, paresthesia, photophobia, premature ventricular contraction, pruritus, rash, irritableness, hypersensitivity, tinnitus, tremor, visual blurring, wheezing, oxygen saturation decline due to coughing, discoloration at the injection site, and burning sensation in the eyes.
In a prospective, post-marketing safety surveillance study of Optison used in routine clinical practice, a total of 1039 subjects received Optison. Of these patients, 648 (62.4%) were male and 391 (37.6%) were female with average age of 59.9 years (min, max: 20, 97). The racial distributions were 864 (83.2%) White, 141 (13.6%) Black, 18 (1.7%) Asian, and 16 (1.5%) other racial or ethnic groups. Overall, 175 patients (16.8%) reported at least one adverse event. No serious adverse reactions, including deaths, were reported in this study.
The following adverse reactions have been identified during the postmarketing use of Optison. 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.
Cardiac arrests and other serious but non-fatal adverse reactions were uncommonly reported. Most of these reactions included cardiopulmonary symptoms and signs such as cardiac arrest, hypotension, supraventricular and ventricular arrhythmias, respiratory distress or decreased oxygenation. Reports also identified neurologic reactions (loss of consciousness or convulsions) as well as hypersensitivity reactions [see Warnings and Precautions (5.2)].
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 2-4% and 15-20%, respectively.
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.
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.
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.
Optison (perflutren protein-type A microspheres) injectable suspension is an ultrasound contrast agent for intravenous injection. The vial contains a clear liquid lower layer, a white liquid upper layer, and a headspace filled with perflutren gas. After resuspension, the sterile suspension is homogeneous, opaque, and milky-white.
Perflutren is chemically characterized as 1,1,1,2,2,3,3,3-perflutren with a molecular weight of 188, an empirical formula of C3F8 and it has the following structural formula:
Each mL of Optison contains 5.0-8.0×108 protein-type A microspheres, 10 mg albumin human, 0.22 ± 0.11 mg/mL perflutren; and the following excipients: 0.2 mg N-acetyltryptophan, and 0.12 mg caprylic acid in 0.9% aqueous sodium chloride. The headspace of the vial is filled with perflutren gas. The pH is adjusted to 6.4-7.4. The protein in the microsphere shell makes up approximately 5-7% (w/w) of the total protein in the suspension. The microsphere particle size parameters are listed in Table 2.
|Mean diameter (range)||3.0-4.5 µm (max. 32.0µm)|
|Percent less than 10µm||95%|
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 (2-5 MHz), the microspheres resonate which further increases the extent of ultrasound scattering and reflection.
The median duration of Optison contrast enhancement for each of the four doses of Optison, 0.2 (40% of recommended dose), 0.5, 3.0, and 5 mL , were approximately one, two, four, and five minutes, respectively [see Clinical Studies (14.1)].
After injection of Optison, diffusion of the perflutren gas out of the microspheres is limited by the low partition coefficient of the gas in blood that contributes to the persistence of the microspheres.
The pharmacokinetics of the intact microspheres of Optison in humans are unknown.
The binding of perflutren to plasma proteins and its partitioning into blood cells are unknown. However, perflutren protein binding is expected to be minimal due to the low partition coefficient of the gas in blood.
Following intravenous injection, perflutren is cleared with a pulmonary elimination half-life of 1.3 ± 0.69 minutes (mean ± SD).
Perflutren is a stable gas that is not metabolized. The human albumin component of the microsphere is expected to be handled by the normal metabolic routes.
Animal studies were not carried out to determine the carcinogenic potential of Optison.
The result of the following genotoxicity studies with Optison were negative: 1) Salmonella/Escherichia coli reverse mutation assay, 2) in vitro mammalian chromosome aberration assay using Chinese hamster ovary cells (CHO) with and without metabolic activation, 3) CHO/HGPRT forward mutation assay, and 4) in vivo mammalian micronucleus assay.
The efficacy of Optison was evaluated in two identical multicenter, controlled, dose escalation studies of 203 patients (Study A: n=101, Study B: n=102) with sub-optimal non-contrast echocardiography defined as having at least two out of six segments of the left ventricular endocardial border inadequately delineated in the apical four-chamber view. Among these patients there were 79% men, 21% women, 64% White, 25% Black, 10% Hispanic, and 1% other race or ethnic group. The patients had a mean age of 61 years (range: 21 to 83 years), a mean weight of 196 lbs. (range: 117 to 342 lbs.), a mean height of 68 inches (range: 47 to 78 inches), and a mean body surface area of 2.0m2 (range: 1.4 to 2.6m2). Approximately 23% of the patients had chronic pulmonary disease, and 17% had congestive and dilated cardiomyopathy with left ventricular ejection fractions (LVEFs) of between 20% and 40% (by previous echocardiography). Patients with a LVEF of less than 20% or with New York Heart Association Class IV heart failure were not included in the studies.
After non-contrast imaging, Optison was administered in increasing increments as 4 doses (0.2, 0.5, 3.0 and 5 mL) with at least ten minutes between each dose. Ultrasound settings were optimized for the baseline (non-contrast) apical four-chamber view and remained unchanged for the contrast imaging. Static echocardiographic images and video-tape segments were interpreted by a reader who was blinded to the patient's clinical history and to the dose of Optison. Left ventricular endocardial border delineation and left ventricular opacification, were assessed before and after Optison administration by the measurement of visualized endocardial border length and ventricular opacification.
In comparison to non-contrast ultrasound, Optison significantly increased the length of endocardial border that could be visualized both at end-systole and end-diastole (see Table 3). In these patients there was a trend towards less visualization in women. Optison increased left ventricular opacification (peak intensity) in the mid-chamber and apical views (see Table 4). The imaging effects of Optison on endocardial border delineation and left ventricular opacification were similar at doses between 0.5 ml and 5 ml and were also similar among patients with or without pulmonary disease and dilated cardiomyopathy.
|Length at End-Systole (cm)||Length at End-Diastole (cm)|
|OPTISON dose||n||mean ± S.D.||n||mean|
|Study A (n=101)|
|0 mL (baseline)||87||7.7 ± 3.0||86||9.3 ± 3.4|
|0.5 mL||86||12.0 ± 4.9||91||15.8 ± 5.1|
|Study B (n=102)|
|0 mL (baseline)||89||8.1 ± 3.4||89||9.6 ± 3.7|
|0.5 mL||95||12.4 ± 4.9||97||16.4 ± 4.6|
|Intensity at End-Diastole||Intensity at End-Systole||Intensity at End-Diastole||Intensity at End-Systole|
|OPTISON dose||n||mean ± S.D.||n||mean ± S.D.||n||mean ± S.D.||n||mean ± S.D.|
|Study A (n = 101)|
|0 mL (baseline)||91||39.5 ± 16.9||91||40.0 ± 18.1||91||46.7 ± 19.7||91||46.9 ± 20.1|
|0.5 mL||91||57.3 ± 26.8||90||57.4 ± 26.7||91||67.0 ± 30.1||90||64.1 ± 30.2|
|Study B (n = 102)|
|0 mL (baseline)||95||40.4 ± 17.4||95||40.9 ± 17.5||95||43.7 ± 19.9||95||45.0 ± 19.6|
|0.5 mL||97||53.3 ± 20.7||96||53.6 ± 21.0||97||64.4 ± 25.3||96||61.6 ± 26.7|
The effect of Optison on pulmonary hemodynamics was studied in a prospective, open-label study of 30 patients scheduled for pulmonary artery catheterization, including 19 with an elevated baseline pulmonary arterial systolic pressure (PASP) (>35 mmHg) and 11 with a normal PASP (â‰¤35 mmHg). 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 Optison on visualization of cardiac or pulmonary structures.
Optison is supplied as 3 mL single-patient use vials containing a clear liquid lower layer, a white liquid upper layer, and a headspace filled with perflutren gas and is homogeneous, opaque, and milky-white after resupsension. Each mL contains 5-8 ×108 protein-type A microspheres, 10 mg albumin human, and 0.22 ± 0.11 mg perflutren:
Store OPTISON refrigerated between 2°- 8°C (36°- 46°F).
Caution: Do not freeze.
Distributed by GE Healthcare Inc., Marlborough, MA 01752 U.S.A.
Manufactured by GE Healthcare AS, Oslo, Norway
OPTISONâ„¢ is a trademark of GE Healthcare or one of its subsidiaries
GE and the GE Monogram are trademarks of General Electric Company.
© 2016 General Electric Company - All rights reserved.
Revised September 2016
|OPTISON PERFLUTREN PROTEIN-TYPE A MICROSPHERES
human albumin microspheres and perflutren injection, solution
|Labeler - GE Healthcare Inc. (053046579)|
|Mallinckrodt Inc.||557570652||ANALYSIS(0407-2707) , API MANUFACTURE(0407-2707) , MANUFACTURE(0407-2707)|
|GE Healthcare AS||515048908||MANUFACTURE(0407-2707) , RELABEL(0407-2707) , REPACK(0407-2707)|