Optison Perflutren Protein-Type A Microspheres: Package Insert and Label Information

OPTISON PERFLUTREN PROTEIN-TYPE A MICROSPHERES- human albumin microspheres and perflutren injection, solution
GE Healthcare Inc.

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

• The recommended dose of OPTISON is 0.5 mL intravenously 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 5 mL in any 10 minute period.
• The maximum total dose should not exceed 8.7 mL in any one patient study.

2.2 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 (20° to 25°C or 68° to 77°F) before use.
• Inspect the vial for complete resuspension. Do not use if the suspension 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.

2.3 Administration Instructions

• Inspect visually for particulate matter and discoloration prior to administration, whenever supension and container permit. Do not inject if the suspension 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 (5.3)] .
• 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.

3 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 5-8×10 ⁸ 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.

4 CONTRAINDICATIONS

​ Do not administer OPTISON to patients with known or suspected hypersensitivity to perflutren or albumin [see Warnings and Precautions (5.5)] .

5 WARNINGS AND PRECAUTIONS

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 [see Dosage and Administration (2.3)] .

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.

5.5 Transmissible Infectious Agents

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.

6 ADVERSE REACTIONS

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)]

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.

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 *†

* Patients are counted separately within each body system. † The body system is reported if the aggregate is ≥ 0.5%. Details are not shown if the subsystem is not ≥ 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%)
Headache	15	(5.4%)
Warm Sensation/Flushing	10	(3.6%)
Chills/fever	4	(1.4%)
Flu-like Symptoms	3	(1.1%)
Malaise/Weakness/Fatigue	3	(1.1%)
Cardiovascular System	12	(4.3%)
Dizziness	7	(2.5%)
Chest Pain	3	(1.1%)
Digestive System	12	(4.3%)
Nausea and/or Vomiting	12	(4.3%)
Nervous System	3	(1.1%)
Respiratory System	5	(1.8%)
Dyspnea	3	(1.1%)
Skin & Appendages	11	(3.9%)
Injection Site Discomfort	3	(1.1%)
Erythema	2	(0.7%)
Special Senses	9	(3.2%)
Altered Taste	5	(1.8%)

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.

6.2 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 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.

Cardiac arrests, including fatalities, and other serious 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).

Hypersensitivity

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.

8 USE IN SPECIFIC POPULATIONS

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 2-4% and 15-20%, 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.