Optison Perflutren Protein-Type A Microspheres: Package Insert and Label Information (Page 2 of 3)

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

Safety and effectiveness in pediatric patients have not been established.

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.

11 DESCRIPTION

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 C ₃ F ₈ and it has the following structural formula:

Each mL of OPTISON contains 5-8 ×10 ⁸ protein-type A microspheres, 10 mg albumin human, 0.22 ± 0.11 mg 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.

Table 2 Microsphere Particle Size Parameters

Mean diameter (range)	3 to 4.5 µm (max. 32 µm)
Percent less than 10 µm	95%

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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)].

12.3 Pharmacokinetics

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.

Distribution

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.

Elimination

Following intravenous injection, perflutren is cleared with a pulmonary elimination half-life of 1.3 ± 0.69 minutes (mean ± SD).

Metabolism

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.

Excretion

Perflutren is eliminated through the lungs within 10 minutes. The mean ± SD recovery was 96% ± 23%. The perflutren concentration in expired air peaked approximately 30-40 seconds after administration.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Animal studies were not carried out to determine the carcinogenic potential of OPTISON.

Mutagenesis

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.

14 CLINICAL STUDIES

14.1 Echocardiography

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 2.0m ² (range: 1.4 to 2.6m ²). 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.

Table 3 Left Ventricular Endocardial Border Length Before and After OPTISON *^, †

	Length at End-Systole (cm)		Length at End-Diastole (cm)
* The differences in the number of enrolled patients and evaluated patients at each dose reflects exclusions based on withdrawal from the trial, or those with technically inadequate or missing images. † An intent-to-treat analysis, with non-favorable values imputed for missing patients, provided qualitatively similar results.
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

Table 4 Intensity of Left Ventricular Opacification * Before and After OPTISON™ †^, ‡

	Mid-Chamber				Apex
	Intensity at End-Diastole		Intensity at End-Systole		Intensity at End-Diastole		Intensity at End-Systole
* Intensity measured by videodensitometry in arbitrary gray scale units (0-255). † The differences in the number of enrolled patients and evaluated patients at each dose reflects exclusions based on withdrawal from the trial, or those with technically inadequate or missing images. ‡ An intent-to-treat analysis, with non-favorable values imputed for missing patients, provided qualitatively similar results.
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

14.2 Pulmonary Hemodynamic Effects

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 (≤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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

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 ×10 ⁸ protein-type A microspheres, 10 mg albumin human, and 0.22 ± 0.11 mg perflutren:

Five (5) – 3 mL vials per carton Eighteen (18) – 3 mL vials per carton

NDC 0407-2707-03 NDC 0407-2707-18