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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). Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY® administration and monitor all patients for acute reactions.
The reported reactions 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].
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 DEFINITY® in Patients with Cardiac Shunts
In patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts phospholipid-encapsulated microspheres can bypass the pulmonary particle-filtering mechanisms and directly enter the arterial circulation resulting in microvascular occlusion and ischemia. In an animal study utilizing intra-arterial administration of activated DEFINITY®, microsphere trapping was seen in small arterioles < 15 μm, especially at branch points and in capillaries at all doses tested, including doses directly applicable to those used in humans. An animal study utilizing intravenous administration did not result in arterial microvascular obstruction presumably because of filtering by the lungs. Do not administer DEFINITY® 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 activated DEFINITY® at mechanical indices greater than 0.8 has not been evaluated [see DOSAGE AND ADMINISTRATION]. The safety of activated DEFINITY® with the use of end-systolic triggering has not been evaluated.
ECG parameters for doses up to 10 microL/kg were monitored in 221 subjects at multiple time points from 1 hour to 72 hours after the first bolus injection. In the 221 subjects, QTc prolongations of > 30 msec were noted in 64 (29%) subjects. Forty-six out of 64 subjects with QTc prolongations were further evaluated and 39% (18/46) showed associated cardiac rhythm changes. The effects of concomitant drugs were not studied.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies with activated DEFINITY® have not been performed to evaluate carcinogenic potential. Evidence of genotoxicity was not found in the following studies with activated DEFINITY®: 1) bacterial mutagenesis assay (Ames assay), 2) in vitro mammalian mutagenesis assay, 3) in vitro human lymphocyte chromosome aberration assay, and 4) in vivo rat micronucleus assay.
Impairment of male or female fertility was not observed in rats and rabbits treated with activated DEFINITY® at doses up to 24 and 15 times the human dose based on body surface area (in rats and rabbits respectively).
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies of DEFINITY® in pregnant women. Reproduction studies performed in rats and rabbits at doses up to 24 and 15 times the human dose based on body surface area (in rats and rabbits respectively) revealed no evidence of impaired fertility or harm to the fetus due to DEFINITY®. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether DEFINITY® is excreted in human milk. Based on the rapid clearance of this drug, advise nursing mothers to pump and discard breast milk once after treatment [see CLINICAL PHARMACOLOGY]. Because many drugs are excreted in human milk, caution should be exercised when DEFINITY® is administered to a nursing mother.
The safety and effectiveness of activated DEFINITY® have not been established in the pediatric population.
The safety of injecting activated DEFINITY® in neonates and infants with immature pulmonary vasculature has not been studied.
The pharmacokinetics of activated DEFINITY® in pediatric subjects has not been studied.
In clinical trials, the overall incidence of adverse reactions was similar for the < 65 year age group and the ≥ 65 year age group. Of the total number of subjects in clinical trials of DEFINITY®, 144 (33%) were 65 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.
The overall incidence of adverse reactions was similar between males and females.
The overall incidence of adverse reactions was similar among all racial and ethnic groups.
Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.
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