Only data pertaining to perflutren protein-type A microspheres for injection (Optison) is discussed in this monograph.
Perflutren protein-type A microspheres is an intravenous diagnostic agent used with ultrasonography to produce an echogenic contrast effect in the blood. Specifically, perflutren protein-type A microspheres is indicated for administration to patients with suboptimal echocardiograms to enhance visualization of left ventricular endocardial borders. Perflutren is an octafluoropropane, a fluorocarbon gas, that is encapsulated within an albumin shell to optimize the size of the gas bubble (2 to 4.5 micrometers) and improve stability. During ultrasound examination, the gas-filled microspheres produce a lower impedence to the acoustic waves than does the surrounding blood, resulting in ultrasound waves that are scattered and reflected at the microsphere-blood interface. In addition, at frequency used during echocardiograms (2 to 5 MHz), the microspheres resonate which further increases the ultrasound scattering and reflecting. The ultimate effect is enhanced visualization of the ultrasound image. Prior to drug administration, ensure resuscitation equipment and trained personnel are readily available. Perflutren protein-type A microspheres is associated with serious cardiopulmonary adverse reactions. Perflutren protein-type A microspheres was FDA-approved in 1997.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Hypersensitivity reactions, including serious cardiopulmonary reactions, may occur. Prior to administration, assess all patients for previous reactions to any of the active or inactive ingredients. Trained personnel and therapies used to treat hypersensitivity reactions (e.g., epinephrine, antihistamines, and corticosteroids) should be readily available. Observe patient for signs and symptoms of hypersensitivity reactions during and after administration. Most serious reactions occur within 30 minutes of drug administration.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever suspension and container permit. Do not use if the suspension is not opaque, milky-white, and absent of particulate matter.
-For intravenous administration only into a peripheral vein. Do not inject into the arterial circulation.
Intravenous Administration
Intravenous injection preparation:
-Use a single vial for each individual patient; do not share vials among patients.
-Do not use if container has been damaged or protective seal broken. The product contains no preservatives. Discard all unused product.
-Do not use the vial if the upper white layer is absent. This would indicate that the microspheres have been damaged and would give poor or no contrast.
-Do not inject air into the vial. (The headspace of the vial is filled with perflutren gas.)
-Invert the vial and gently rotate to resuspend the microspheres. This will also bring the vial to room temperature (20 to 25 degrees C or 68 to 77 degrees F) before use.
-Inspect the content of vial for complete resuspension. Failure to resuspend all particles will result in poor contrast. If the product is clear rather than appearing opaque and milky white, do not use.
-Using a sterile vent spike or a sterile 18-gauge needle, vent the vial before withdrawing the suspension into an injection syringe.
-The time between injection preparation/resuspension and administration must not exceed 1 minute. If 1 minute is exceeded resuspend the microspheres in syringe by rotating and inverting the syringe gently.
Intravenous injection procedure for use in echocardiography:
-Before injection, provide IV access in a peripheral vein with a 20-gauge or larger angiocatheter. Suggested methods of administration include a short extension tubing, heparin lock, or intravenous line, all with a 3-way stopcock.
-For short extension tubing or hep-lock, fill one syringe with 0.9% Sodium Chloride Injection, and flush the line for patency before and after the injection of perflutren protein-type A microspheres.
-For a continuous intravenous line, open an intravenous line with 0.9% Sodium Chloride Injection or 5% Dextrose Injection at a slow infusion rate to maintain vascular patency. The line should be flushed immediately after injection of perflutren protein-type A microspheres.
-DO NOT ASPIRATE blood back in the syringe prior to drug injection as this may cause the formation of a blood clot within the syringe.
-The injection rate should not exceed 1 mL per second.
-Follow the injection with a flush of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
In clinical studies (n = 279), roughly 16.8% of patients reported an adverse event to perflutren protein-type A microspheres. Most were mild and transient. The most frequently reported adverse reaction to perflutren protein-type A microspheres was headache (5.4%). Other general adverse reactions reported were warm sensation or flushing (3.6%), chills and fever (1.4%), flu-like symptoms (1.1%), and 1.1% of patients experienced malaise, weakness, and fatigue (1.1%).
Dizziness was reported by 2.5% of patients treated with perflutren protein-type A microspheres during clinical studies. Other less common (less than 0.5%) adverse events included paresthesias, irritability, and tremor. During post-marketing surveillance, loss of consciousness (coma) and seizures have been reported. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Nausea and vomiting was reported in 4.3% of patients receiving perflutren protein-type A microspheres during clinical trials. Other less commonly reported gastrointestinal adverse events included dysgeusia (1.8%) and xerostomia or dry mouth (less than 0.5%).
Injection site reaction, specifically discomfort, and erythema were reported in 1.1% and 0.7% of patients, respectively, during clinical trials with perflutren protein-type A microspheres. Induration and discoloration at the heparin lock site occurred in less than 0.5% of patients during clinical trials.
During clinical trials with perflutren protein-type A microspheres, chest pain (unspecified) and dyspnea were reported in 1.1% of patients; only 1 patient reported a serious hypersensitivity reaction that required treatment with antihistamines. Other adverse events occurring in less than 0.5% of drug recipients during clinical trials included premature ventricular contraction, palpitations, eosinophilia, pruritus, rash, wheezing, oxygen desaturation due to cough, and urticaria. During postmarketing surveillance, fatal cardiac arrest and a non-fatal but serious cardiopulmonary reaction have been reported including respiratory arrest, hypotension, supraventricular and ventricular arrhythmias, atrial fibrillation, sinus tachycardia, bradycardia, respiratory distress, hypoxia, stridor, syncope, and decreased oxygenation. Anaphylactoid reactions, with manifestations including death, shock, bronchospasm, throat tightness, edema (pharyngeal, palatal, mouth, localized, peripheral edema), angioedema, swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema, have also been reported during postmarketing experience with perflutren protein-type A microspheres.
Musculoskeletal adverse events reported in less than 0.5% of patients receiving perflutren protein-type A microspheres during clinical trials included arthralgia, back pain, and myalgia.
Special senses adverse events reported in less than 0.5% of patients receiving perflutren protein-type A microspheres during clinical trials included photophobia, tinnitus, blurred vision, and ocular irritation (i.e., burning sensation).
Do not give perflutren protein-type A microspheres via intraarterial administration. The drug is only intended for administration by peripheral vein.
Perflutren protein-type A microspheres is contraindicated in patients with known or suspected perflutren hypersensitivity or albumin hypersensitivity. Perflutren protein-type A microspheres contain albumin. Serious anaphylactic reactions have been observed during or shortly after perflutren-containing microsphere administration. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to perflutren protein-type A microspheres administration and monitor all patients for hypersensitivity reactions.
Perflutren protein-type A microspheres contain albumin, a derivative of human blood. This carries an extremely remote risk for transmission of viral infection or contamination with Creutzfeldt-Jakob disease (CJD) or other infections. Effective screening of donors and manufacturing processes reduce the risk for infection transmission. No cases of transmission of viral illness or CJD have been identified for albumin.
Although uncommon, a serious cardiopulmonary reaction, including some fatalities, has occurred during or immediately following the administration of perflutren protein-type A microspheres. These reactions (e.g., fatal cardiac or respiratory arrest, shock, syncope, cardiac arrhythmias, hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, convulsions) typically develop within 30 minutes of drug administration. Patients at increased risk include those with unstable cardiopulmonary conditions such as acute myocardial infarction, acute coronary artery disease, worsening or unstable heart failure, or serious ventricular arrhythmias. Ensure resuscitation equipment and trained personnel are readily available prior to perflutren protein-type A microspheres administration, and monitor all patients for acute reactions. Additionally, before contrast administration, adjust the ultrasound mechanical index value to 0.8 or lower. Failure to adjust the mechanical index value may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Further, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias.
Use caution when administering perflutren protein-type A microspheres to patients with a cardiac shunt (i.e., right-to-left, bidirectional, or transient right-to-left arteriovenous shunt). In these patients, microspheres can bypass filtering by the lung and directly enter the arterial circulation, which may result in significant toxicity such as microvascular occlusion and ischemia. If administering perflutren protein-type A microspheres to a shunt patient, monitor for evidence of an embolic phenomena.
Perflutren protein-type A microspheres is classified as FDA pregnancy category C. Animal studies have indicated a potential for embryo, fetal, or maternal risks. Adequate or well-controlled investigations have not been performed during human gestation. Perflutren protein-type A microspheres should be used during pregnancy only when the potential benefit justifies the potential fetal risk.
It is not known whether perflutren protein-type A microspheres is excreted in human breast milk. Use caution when administering perflutren protein-type A microspheres to a breast-feeding woman.
For use during echocardiography to enhance ultrasound imaging by opacifying the left ventricle and improving the delineation of the left ventricular endocardial borders:
NOTE: Diagnostic echocardiography procedures that involve the use of this product should be carried out under the direction of a licensed practitioner having a thorough knowledge of the procedure and the safe use of the product.
Intravenous dosage:
Adults: 0.5 mL IV at a rate not exceeding 1 mL per second. If contrast enhancement is inadequate, may repeat dose in increments of 0.5 mL, up to 5 mL IV in a 10-minute period. Maximum total dose of 8.7 mL per patient study.
Maximum Dosage Limits:
-Adults
Do not exceed 5 mL IV in any 10 minute period, or a maximum total dose of 8.7 mL IV per any one patient echocardiography study.
-Geriatric
Do not exceed 5 mL IV in any 10 minute period, or a maximum total dose of 8.7 mL IV per any one patient echocardiography study.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Perflutren Protein-Type A Microspheres products.
Perflutren protein-type A microspheres enhances visualization of ultrasound imaging. When the gas-filled perflutren protein-type A microspheres injected into the body are exposed to ultrasound waves, the microspheres resonate and echo strong signals back to the ultrasound machine. The difference in density between the gas-filled bubbles and the blood around them creates an increased level of contrast visible in the resulting ultrasound image. Because the flow pattern of the microspheres represent actual blood flow patterns, the agent can be useful in gauging circulation patterns and perfusion during ultrasound.
In an anesthetized dog model, the acoustic properties of perflutren protein-type A microspheres were established at 0.6 mechanical index and 2.5 MHz frequency. Frequencies used in human adult echocardiography are typically 2 to 5 MHz; the median assessed duration of contrast enhancement is as follows for the following dosages: 0.2 mL dose- 1 minute; 0.5 mL dose- 2 minutes; 3 mL dose- 4 minutes; 5 mL dose- 5 minutes.
Perflutren protein-type A microspheres is administered intravenously. Human pharmacokinetic studies of the intact microspheres have not been performed. The low partition coefficient of the perflutren (octafluoropropane) gas in blood contributes to the persistence of the microspheres in the circulation, and limits diffusion of the gas out of the microspheres. The low partition coefficient of the gas in blood also indicates that perflutren is not likely to bind to plasma proteins or partition into blood cells. Perflutren (octafluoropropane) gas is not metabolized. Pharmacokinetic studies of the human albumin component have not been done; however, the albumin component of the product is expected to be metabolized according to the normal metabolic pathway of albumin in humans.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
Following a single 20 mL IV dosage in 10 healthy adults (5 males and 5 females), most (mean 96%) of the perflutren protein-type A microspheres injection was eliminated via the lungs within 10 minutes; the peak perflutren concentration in expired air occurred at roughly 30 to 40 seconds post dose administration. The pulmonary half-life was 1.3 +/- 0.69 minutes.