Rockville, MD - As expected, the US FDA has requested that a boxed warning be added to the labeling of two contrast agents used in echocardiography: perflutren liquid microspheres (Definity; Bristol-Myers Squibb) and perflutren protein-type A microspheres for injection (Optison; General Electric) [1,2].

The warning comes following reports of 11 deaths and 199 serious cardiopulmonary reactions after the administration of such agents in echocardiography. Ten of the deaths and 190 of the serious reactions were related to Definity use. Optison has been off the market since 2005 because of a manufacturing problem, but it is expected to be reintroduced shortly.

Numerous reports describe the acute onset of symptoms suggestive of an anaphylactoid reaction, including dyspnea or urticaria. Others describe cardiopulmonary reactions with cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias, cardiac ischemia, hypotension, respiratory distress, and oxygen desaturation without signs or symptoms typical of an allergic reaction.

Many of these serious reactions occurred during or within minutes of the administration of the ultrasound contrast agent—four of the 11 reported deaths were caused by cardiac arrest either during infusion or within 30 minutes of the administration of the contrast agent; most of the serious but nonfatal reactions also occurred in this time frame, according to the FDA.

As a result, Bristol-Myers Squibb and General Electric have agreed to revise the labeling for these products to optimize their safe use.

Revisions to the labeling so that it emphasizes the risk for serious cardiopulmonary reactions include changing the boxed warning, contraindications, and warnings sections and adding a statement in the indications section cautioning that the safety and efficacy of the use of Definity with exercise or pharmacological stress testing have not been established.

In addition, the new labeling states that the use of these products is contraindicated in patients with unstable cardiopulmonary status, including those with unstable angina, acute MI, respiratory failure, and recent worsening of congestive heart failure.

Definity has been used in about two million patients in the US since it was approved in 2001. The product is also available in Europe and Australia, where it is marketed as Luminity.