Definity, marketed by Lantheus Medical Imaging, and Optison, distributed by GE Healthcare, are used during echocardiograms, ultrasound imaging procedures that take a detailed, moving picture of the heart. In October 2007 the Food & Drug Administration (FDA) said that it knew of at least 7 deaths associated with the administration of either Definity or Optison. Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent. The FDA said that most 200-plus serious but non-fatal reactions reported to the agency also occurred in the same time frame.
As a result of these reports, the FDA requested that the labeling on Definity and Optison be modified to include a black box warning about the cardiac problems associated with these agents. The agency also said that Definity and Optison should not be used in patients who were acutely ill, such as those with congestive heart failure.
Since October 2007, the FDA has received post-market reports of five deaths following the administration of Definity; no deaths were reported for Optison. All patients who died following the administration of Definity had severe underlying medical conditions. Three of the deaths were associated with cardiac arrest that occurred within 30 minutes following Definity administration. Most patients had multiple co-morbidities. Following the October 2007, the FDA has also received approximately 60 reports of serious non-fatal reactions following Definity administration.
Despite the continuing reports of deaths related to the contrast agents, many cardiologists complained that that restriction robbed them of an important diagnostic tool. In today's notice to healthcare providers, the FDA said several of the warnings that were added to the labeling in October 2007 were removed because the agency determined that, in some patients, the benefits from the diagnostic information that could be obtained through the use of Definity and Optison may outweigh the risk for serious cardiopulmonary reactions, even among some patients at particularly high risk for these reactions.
As part of the revision, the FDA removed warnings that Definity and Optison should not be administered to patients with worsening or clinically unstable congestive heart failure, acute myocardial infarction or acute coronary syndromes, serious ventricular arrhythmias or high risk of arrhythmias due to prolongation of the QT interval, respiratory failure, severe emphysema, and pulmonary emboli or other conditions that cause pulmonary hypertension.
The label revisions recommend that high-risk patients with pulmonary hypertension or unstable cardiopulmonary conditions be closely monitored during and for at least 30 minutes after administration of these contrast agents.
Along with the label changes, the FDA says it is now requiring that manufacturers of micro-bubble contrast agents conduct clinical studies to more thoroughly assess the risks for serious cardiopulmonary reactions.
Definity, marketed by Lantheus Medical Imaging, and Optison, distributed by GE Healthcare, are used during echocardiograms, ultrasound imaging procedures that take a detailed, moving picture of the heart. In October 2007, the FDA said that it knew of at least 7 deaths associated with the administration of either Definity or Optison. Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent. The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.
As a result of these reports, the FDA requested that the labeling on Definity and Optison be modified to include a black box warning about the cardiac problems associated with these agents. The agency also said that Definity and Optison should not be used in who were acutely ill, such as those with congestive heart failure.
However, many cardiologists complained that that restriction robbed them of an important diagnostic tool. Last month, in response to those complaints, the FDA dropped the ban on giving the agents to acutely ill patients. The FDA also changed monitoring requirements for the drugs. The black box warning had originally called for monitoring all patients for 30 minutes after they receive the agents, but the revised warning said only patients with pulmonary hypertension or unstable cardiopulmonary conditions need to be monitored.
But the agency continued to be concerned about the safety of Definity and Optison, and earlier this week said that Definity had been linked to four more deaths since October 2007.
Yesterday, the FDA convened an advisory panel of outside medical experts to discuss the heart imaging agents. The agency wanted advice on what safety issues to consider as companies seek to use imaging agents to diagnose other conditions such as liver problems.
The panel said that ideally, companies selling or seeking to sell such contrast agents would launch a randomized placebo-controlled study of thousands of patients to assess the potential for heart risks. However, the panel also said the companies could conduct less-thorough observational studies if the other was not practical.
According to Dwaine Rieves, the FDA's director of medical imaging products, both GE Healthcare and Lantheus have already agreed to review post-marketing data for safety issues. But he said that that the panel's recommendations could affect the advice given to companies seeking future FDA approvals.
Definity, marketed by Lantheus Medical Imaging, and Optison, distributed by General Electric, consist of microscopic gas-filled spheres that sharpen ultrasound pictures. Definity and Optison are used during echocardiograms, ultrasound imaging procedures that take a detailed, moving picture of the heart. If the image is unclear, contrast agents such as Definity and Optison can be given intravenously to help make the heart easier to see.
According to the FDA, there have been more than 200 reports of serious cardiac reactions involving the use of Definity and Optison. In October 2007, the FDA said that it knew of at least 7 deaths associated with the administration of either Definity or Optison. Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent. The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.
As a result of these reports, the FDA requested that the labeling on Definity and Optison be modified to include a black box warning about the cardiac problems associated with these agents. A black box warning is the FDA’s strictest type of warning. But many cardiologists questioned the restrictions the FDA placed on Definity and Optison.
Just last month, the FDA dropped a ban on giving the agents to acutely ill patients, such as those with congestive heart failure. The FDA also changed monitoring requirements for the drugs. The black box warning had originally called for monitoring all patients for 30 minutes after they receive the agents, but the revised warning said only patients with pulmonary hypertension or unstable cardiopulmonary conditions need to be monitored.
But apparently, Definity is still causing serious side effects in some patients. According to documents released by the FDA, four more deaths have been reported to the agency since October 2007. So far, Definity has accounted for most of the reactions and deaths, probably because Optison was off the market between November 2005 and October 2007. GE Healthcare voluntarily withdrew Optison after an FDA inspection found problems with a contract manufacturer. So far, no adverse events have been reported in relation to Optison since it returned to the market.
Definity, marketed by Bristol Myers Squibb, and Optison, distributed by General Electric, consist of microscopic gas-filled spheres that sharpen ultrasound pictures. According to the FDA, there have been more than 200 reports of serious cardiac reactions involving the use of Definity and Optison. In October 2007, the FDA said that it knew of at least 11 deaths associated with the administration of either Definity or Optison. Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent. The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.
As a result of these reports, the FDA requested that the labeling on Definity and Optison be modified to include a black box warning about the cardiac problems associated with these agents. A black box warning is the FDA’s strictest type of warning. But many cardiologists questioned the restrictions the FDA placed on Definity and Optison. At least one prominent cardiologist said that the black box warning was added to the ultrasound contrast agents without a formal examination of the risks and benefits of using them.
The FDA's decision to drop the ban on micro-bubble contrast agents for acute patients came after a study was published that indicated the risk from the dyes might not be as serious as first thought. That study, which was presented at the April meeting of the American College of Cardiology, examined the clinical outcomes of nearly 18,000 patients who received ultrasound contrast agents during an echocardiogram and compared their results to those from a group of approximately 6,000 patients who did not need to receive contrast agents.
To test the safety of contrast agents, the researchers looked at the short-term (within 30 minutes of the infusion) and long-term (within 24 hours) outcomes and noted any serious adverse events or deaths. Of the nearly 18,000 individuals to receive the contrast agents, not one experienced an adverse event within 30 minutes. One death and three non-fatal heart attacks occurred within 24 hours; however these could not be attributed to the contrast agents.
According to The Wall Street Journal, cardiologists are applauding the FDA's move. The previous restrictions meant physicians had to used other diagnostic methods — including angiograms and an ultrasound technique that involves going in through the patient’s throat — that come with their own risks.
There are currently two micro-bubble contrast agents currently on the market - Definity, marketed by Bristol Myers Squibb, and Optison, distributed by General Electric. Definity and Optison contrast agents are used in ultrasounds of the heart to enhance images during a procedure called echocardiography. During an echocardiography, the contrast agents are injected into a patient’s veins. The drugs consist of microscopic gas-filled spheres that sharpen the resulting ultrasound picture. The use of Definity or Optison contrast agents allow doctors to better diagnose heart defects and malfunctions.
But in October 2007, the makers of Definity and Optison agreed to include a new black box warning on their package inserts after the FDA received hundreds of reports of serious cardiac reactions and deaths associated with the administration of these drugs.
A black box warning is given to drugs that carry significant risk of serious or even life-threatening adverse effects. According to the FDA, there have been more than 200 reports of serious cardiac reactions involving the use of Definity and Optison. In October 2007, the FDA said that it knew of at least 11 deaths associated with the administration of either Definity or Optison. Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent. The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.
But Dr. Melda Dolan, an associate professor of cardiology at the St. Louis University School of Medicine, says the black box warning was added to the ultrasound contrast agents without a formal examination of the risks and benefits of using them. Dr. Dolan said his research, which was presented this week at the American College of Cardiology annual meeting in Chicago, raised questions about the FDA's decision.
The purpose of this study was to evaluate the overall risk and benefits of ultrasound contrast agents. Using results from two university hospitals, the researchers examined the clinical outcomes of nearly 24,000 patients who received ultrasound contrast agents during an echocardiogram and compared their results to those from a group of approximately 6,000 patients who did not need to receive contrast agents.
To test the safety of contrast agents, the researchers looked at the short-term (within 30 minutes of the infusion) and long-term (within 24 hours) outcomes and noted any serious adverse events or deaths. Of the nearly 24,000 individuals to receive the contrast agents, not one experienced an adverse event within 30 minutes. One death and three non-fatal heart attacks occurred within 24 hours; however these could not be attributed to the contrast agents.
"Based on the results of our study, we believe the FDA should reconsider its stance on contrast agents because the benefits outweigh the potential, although not established, risk," said Dolan. Many doctors have limited their use of ultrasound contrast agents since the introduction of the black box warning. Dolan said that withholding these agents would make diagnosis of life-threatening heart disease more difficult.
Definity, made by Bristol Meyers Squibb, and Optison, made by General Electric, are known as micro-bubble contrast agents. They are injected into a patient’s blood stream during an ultrasound of the heart known as an echocardiography. The drugs contain tiny, gas-filled spheres that sharpen the resulting ultrasound picture. This allows doctors to better diagnose heart defects and malfunctions. According to the FDA, micro-bubble contrasting agents are only used in a small number of the echocardiography done each year. Generally, the contrast agents are only used when previous ultrasound pictures are inconclusive.
In announcing the new black box warnings, the FDA said that it knew of at least 200 reports of serious cardiac reactions that involved the use of Definity. The FDA also said that at least 11 deaths had been associated with the administration of these contrasting agents. Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent. The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.
The new black box warning, the FDA’s strictest type, says that Definity and Optison could cause patients to experience cardiac events during, and within 30 minutes of infusion. The new label also warns that Definity and Optison are not suitable in patients who have serious heart problems, including unstable angina, unstable cardiopulmonary disease or a history of acute heart attacks. Finally, the black box recommends that physicians monitor all patients receiving micro-bubble contrast agents for serious cardiopulmonary reactions during the infusion and for 30 minutes following completion of administration. Healthcare providers were also advised to keep resuscitation equipment be on hand for half an hour after injecting the drug.
The new black box warning will apply to Definity immediately. Optison was recalled in 2005 and has been off the market since due to a manufacturing problem. At that time, the FDA had ordered General Electric to stop selling Optison after an inspection of a third-party factory that manufactured the drug turned up problems with its methods for maintaining sterility. General Electric has said that the company plans to reintroduce Optison to the market sometime this year.