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OPTISON™
(Perflutren Protein-Type A Microspheres) Injectable Suspension, USP

DESCRIPTION

OPTISON™ (Perflutren Protein-Type A Microspheres Injectable Suspension, USP) is a sterile non-pyrogenic suspension of microspheres of human serum albumin with perflutren for contrast enhancement during the indicated ultrasound imaging procedures. The vial contains a clear liquid lower layer and a white upper layer that, after resuspension by gentle mixing, provides a homogeneous, opaque, milky-white suspension for intravenous injection.

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 5.0-8.0x108 protein-type A microspheres, 10 mg Albumin Human, USP, 0.22 ±0.11 mg/mL perflutren, 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 liquid. The microsphere particle size parameters are listed in Table 1.

Table 1: Microsphere Particle Size Parameters

INDICATIONS

Optison is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders.

DOSAGE AND ADMINISTRATION

Recommended Dosage

• The recommended dose of Optison is 0.5 mL injected into a peripheral vein.
• If the contrast enhancement is inadequate after the dose of 0.5 mL, additional doses in increments of 0.5 mL may be repeated for further contrast enhancement as needed.
• The maximum total dose should not exceed 5mL in any 10 minute period.
• The maximum total dose should not exceed 8.7 mL in any one patient study.

Preparation Instructions

• Do not use if the container has been damaged, the protective seal and/or rubber cap have been entered, or the upper white layer is absent (may indicate the microspheres have been damaged and may result in poor or no echo contrast).
• Invert the Optison vial and gently rotate to resuspend the microspheres. This process will allow the product to come to room temperature before use.
• Inspect the vial for complete resuspension. Do not use if the solution appears to be clear rather than opaque and milky-white.
• Vent the Optison vial with a sterile vent spike or with a sterile 18 gauge needle before withdrawing the Optison suspension into the injection syringe.
• Do not inject air into the vial.
• Use the product within one minute of suspension. If one minute is exceeded, resuspend by inverting and gently rotating the microsoheres in the syringe. Failure to adequately resuspend Optison may cause inadequate delivery of the microspheres, and may result in inadequate contrast.

Administration Instructions

• Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not inject if the solution is not opaque, milky-white, and absent particulate matter.
• Inject through a 20-gauge or larger angiocatheter into a peripheral vein at a rate not exceeding 1 mL per second. Suggested methods of administration include: a short extension tubing, heparin lock, or intravenous line, all with a 3-way stopcock.
• Administer intravenously; do not administer Optison by intra-arterial injection [see WARNINGS AND PRECAUTIONS].
• Do not aspirate blood back into the Optison containing syringe before administration; this may promote the formation of a blood clot within the syringe.
• For short extension tubing or heparin lock: fill one syringe with 0.9% Sodium Chloride Injection, USP, and FLUSH the line for patency before and after the injection of Optison.
• For a continuous intravenous line: open an intravenous line with 0.9% Sodium Chloride Injection, USP (or 5% Dextrose Injection, USP) at a slow infusion rate to maintain vascular patency. Flush the line immediately after injection of Optison
• Do not use the single-patient use vial for more than one patient. Discard unused product.

HOW SUPPLIED

Dosage Forms And Strengths

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 5-8x108 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.

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 x108 protein-type A microspheres, 10 mg albumin human, and 0.22 ± 0.11 mg perflutren:

Five (5) - 3 mL vials per carton NDC 0407-2707-03
Eighteen (18) - 3mL vials per carton NDC 0407-2707-18

Storage And Handling

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. Revised: Sep 2016

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

• Serious Cardiopulmonary Reactions [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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.

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.

Table 1 : SELECTED ADVERSE REACTIONS REPORTED IN ≥ 0.5% OF THE SUBJECTS WHO RECEIVED OPTISON™ IN CONTROLLED CLINICAL STUDIES)

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.

Postmarketing Experience

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].

DRUG INTERACTIONS

No information provided.

WARNINGS

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).

Always have cardiopulmonary resuscitation personnel and equipment readily available prior to OPTISON administration and monitor all patients for acute reactions.

Anaphylactoid Reactions

In postmarketing use, uncommon but serious anaphylactoid reactions were 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 (see ADVERSE REACTIONS).

Systemic Embolization of OPTISON in Patients with Cardiac Shunts

In patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts perflutren-containing microspheres can bypass the pulmonary particle-filtering mechanisms and directly enter the arterial circulation resulting in microvascular occlusion and ischemia. Do not administer OPTISON by intra-arterial injection (see CONTRAINDICATIONS).

High Ultrasound 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 safety of OPTISON at mechanical indices greater than 0.8 has not been evaluated. The safety of OPTISON with the use of end-systolic triggering has not been evaluated.

PRECAUTIONS

General

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.

Laboratory Tests

Immunologic tests of serum immunoglobulins, cytokines, and complement were monitored in a 3 week study of 20 healthy volunteers and 30 patients who received OPTISON or a 1% albumin control. Clinically relevant changes in the measured parameters were not noted. In another study 5 subjects received a skin test with OPTISON one year after receiving OPTISON. One subject had a positive skin test and was not given a repeat dose of OPTISON.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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.

Pregnancy Category C

OPTISON administered intravenously to rats during organogenesis at doses of 0.25, 5.0 and 10.0 mL/kg/day was fetotoxic at 0.25 and 5.0 mL/kg (approximately 0.2 and 5 times the recommended maximum human dose, respectively, based on body surface area). Fetotoxicity was characterized by an increased incidence of reversible delayed pelvic ossification, the incidence of which was not related to dose. Signs of maternal toxicity at 5 mL/kg included respiratory and motor signs. Maternal death occurred at 10 mL/kg. A no observable adverse effect level (NOAEL) for fetotoxicity was not determined. Teratogenic effects were not observed at doses up to 10 mL/kg/day. The NOAEL for maternal toxicity was 0.25 mL/kg.

OPTISON administered intravenously to rabbits during organogenesis at doses of 0.25, 2.5 and 5.0 mL/kg/day was embryofetal toxic at 2.5 and 5.0 mL/kg (approximately 5 and 10 times the recommended maximum human dose, respectively, based on body surface area). Embryofetal toxicity was characterized by a decrease in fetal body weight and an increase in embryofetal death. Teratogenic effects (cleft palates and dilation of the lateral ventricles of the brain associated with skull abnormalities and compression deformities) were observed at 2.5 mL/kg but not 5 mL/kg. Neither the incidence nor the severity of embryofetal toxicity and teratogenicity exhibited a dose-dependent relationship. Maternal toxicity (significant suppression of body weight gain, abnormal stool) was observed at 2.5 and 5.0 mL/kg with the greatest effect observed at 2.5 mL/kg. The NOAEL for embryofetal and maternal toxicity was 0.25 mL/kg (approximately 0.5 times the recommended maximum human dose).

Adequate or well-controlled studies were not conducted in pregnant women. OPTISON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when OPTISON is administered to a nursing woman.

Pediatric Use

Safety and efficacy have not been established in pediatric patients, or in patients with congenital heart disease (see WARNINGS).

OVERDOSE

No information provided.

CONTRAINDICATIONS

Do not administer Optison to patients with known or suspected hypersensitivity to perflutren, blood, blood products or albumin [see WARNINGS AND PRECAUTIONS].

CLINICAL PHARMACOLOGY

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.

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].

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.

Clinical Studies

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 2.0m² (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.

Table 3 : Left Ventricular Endocardial Border Length Before and After OPTISONa, b

Table 4 : Intensity of Left Ventricular Opacificationa Before and After OPTISON™ b,c

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.

PATIENT INFORMATION

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