Deaths Prompt New Warnings for Micro-Bubble Contrast Agents

Deaths Prompt New Warnings for Micro-Bubble Contrast Agents


By Crystal Phend, Staff Writer, MedPage TodayOctober 12, 2007


ROCKVILLE, Md., Oct. 12 -- Eleven deaths and nearly 200 reports of serious cardiopulmonary events have been linked to microbubble contrast agents (Definity and Optison) used in echocardiography, the FDA reported today.


DuPont Pharmaceuticals, maker of Definity, and GE Healthcare, maker of Optison, agreed to labeling changes emphasizing the risk for serious cardiopulmonary reactions and contraindication for use in patients with unstable cardiopulmonary status, said the agency.


Most of the deaths occurred within 12 hours of administration among patients with severe underlying conditions. In four cases, patients died after cardiac arrest within 30 minutes of receiving Definity.


Many of the 190 serious non-fatal reactions reported with Definity and nine reports with Optison also occurred within minutes of administration and were suggestive of anaphylactic or cardiopulmonary reactions, the FDA said.


The labeling changes included:


A boxed warning for cardiopulmonary reactions.


Warnings for cardiopulmonary and hypersensitivity reactions with recommendations to monitor vital signs, cardiac rhythm, oxygen saturation and to have equipment and trained personnel readily available for resuscitation.


Contraindications for high-risk patients, specifically those with known cardiac shunts, clinically unstable or recent worsening of congestive heart failure, symptomatic arrhythmias or at elevated risk for arrhythmias.


A cautionary statement that the safety and efficacy of Definity in exercise or pharmacological stress testing have not been established.


The manufacturers will conduct a postmarketing safety study to monitor risk of serious cardiovascular reactions, the FDA said.


Meanwhile, the FDA suggested that physicians should monitor all patients receiving these contrast agents for serious cardiopulmonary reactions during infusion and for 30 minutes after administration.


The FDA also recommended that all patients should be assessed for the following conditions before use:


Right-to-left, bi-directional, or transient right-to-left cardiac shunts


Clinically unstable or recent worsening congestive heart failure.


Acute myocardial infarction.


Serious ventricular arrhythmias or at high risk for arrhythmias due to QT prolongation.


Respiratory failure.


Severe emphysema, pulmonary emboli or other conditions that compromise pulmonary arterial vasculature.

Bristol-Myers Strengthens Warning on Ultrasound Drug

Bristol-Myers Strengthens Warning on Ultrasound Drug (Update2)



By Beth Jinks


Oct. 11 (Bloomberg) -- Bristol-Myers Squibb Co. strengthened the warning on its drug Definity, used to enhance heart images from ultrasound scans, after a U.S. inquiry into the medicine's safety.


The new prescribing information, highlighted in a black box on the package insert and warning of the risk of "serious cardiopulmonary reactions,'' was posted today on the Food and Drug Administration's Web site. The black box represents the agency's most serious safety caution.


The FDA said Oct. 8 that regulators would soon alert health-care professionals of serious risks and new safety guidelines in using the agents Definity and Optison before echocardiography, a form of ultrasound used to diagnose heart ailments.


Bristol-Myers, which makes Definity, and General Electric Co., which sells Optison, confirmed this week they were discussing package insert revisions with regulators. The safety information for Optison was unchanged on the FDA Web site today.


“The changes are designed to help ensure the safe and appropriate use of Definity,'' Bristol-Myers spokesman Tony Plohoros said. ``We believe that Definity still has significant medical value when used properly and in accordance with the label.''


Bristol-Myers will send doctors FDA-approved letters when "the changes are final,'' Plohoros said. Sales of Definity were $65 million in the U.S. last year and less than $1 million abroad, company spokesman Jeffrey Macdonald said Oct. 8.


New Alert


Definity's new boxed alert warns that "serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes following Definity administration,'' advising that patients be closely monitored and resuscitation equipment be on hand for half an hour after injecting the drug.


Bristol-Myers fell 13 cents to $29.50 at the 4 p.m. close in New York Stock Exchange composite trading. General Electric fell 21 cents to $41.60.


Definity, approved by the FDA in 2001, and Optison, allowed since 1997, enhance ultrasound images to help doctors see the heart more clearly. The drugs are a gas enclosed in small capsules of protein or fatty material that make heart borders clearer, letting doctors rule out small clots and identify abnormalities on the heart wall.


“FDA has been investigating reports of deaths and serious cardiopulmonary reactions after people were given'' the drugs, Karen Riley, an FDA spokeswoman, said Oct. 8. “FDA has also asked manufacturers to update their product labeling and they have agreed to do so.''


“We are currently working with the FDA on how this should be implemented for Optison,'' Graeme Holland, a GE spokesman, said Oct. 8. "To date more than 1 million doses of Optison have been given, and very few adverse reactions have been reported.''


To contact the reporter on this story: Beth Jinks in New York at bjinks1@bloomberg.net


Last Updated: October 11, 2007 16:51 EDT