Serious Cardiopulmonary Reactions:

Serious cardiopulmonary reactions, including fatalities, have occurred during or following perflutren-containing microsphere administration. The risk for these reactions may be increased among patients with pulmonary hypertension or unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, serious ventricular arrhythmias or respiratory failure, including patients receiving mechanical ventilation). In these patients, monitor vital signs, electrocardiography, and cutaneous oxygen saturation during and for at least 30 minutes after DEFINITY® administration. In the absence of these underlying conditions, observe patients closely during and following DEFINITY® administration.

In postmarketing use, uncommon but serious reactions observed during or shortly following perflutren-containing microsphere administration included fatal cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias (atrial fibrillation, supraventricular tachycardia, ventricular tachycardia or fibrillation), hypotension, respiratory distress or cardiac ischemia (see ADVERSE REACTIONS).

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

Anaphylactoid Reactions

Post-marketing reports of acute anaphylactoid reactions including shock, bronchospasm, upper airway swelling, loss of consciousness, urticaria and pruritus, have occurred in patients with no prior exposure to perflutrencontaining microsphere products. Monitor all patients for signs and symptoms of anaphylactoid reactions (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. The safety of activated DEFINITY® with the use of end-systolic triggering has not been evaluated.

QTc Prolongation

ECG parameters for doses up to 10 µL/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.

Included as part of the PATIENT INFORMATION section.

Carcinogenesis, Mutagenesis, 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 up to 1 mL/kg (24x and 15x maximal human dose based on body surface area, respectively).

Pregnancy Category B

Reproduction toxicity studies have been performed in rats and rabbits at up to 3 mL/kg and, 1 mL/kg (24x and 15x maximal human dose based on body surface area for rats and rabbits, respectively). The studies revealed no evidence of an effect of activated DEFINITY® treatment on the developing fetus. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies to detect if activated DEFINITY® is excreted in human milk have not been conducted. Because many drugs are excreted in human milk, caution should be exercised when activated DEFINITY® is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of activated DEFINITY® have not been established in the pediatric population (see WARNINGS).

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