The FDA has added Definity from Lantheus Medical Imaging to its list of products with potential signals of serious risks that were identified January through March of this year in its Adverse Event Reporting System (AERS) database. However, the company is questioning the agency’s timing, as it comes six months after the reported events.
“This dates back to January through March of this year. During that time, the FDA was evaluating Definity and all perflutren bubble contrast agents that are on the U.S. market due to concerns stemming from reports the agency had received,” Mark Hibberd, MD, PhD, senior medical director of global medical affairs at Lantheus, told Health Imaging News. “It’s confusing to have this list, which applies back to the beginning of the year, published now.”
The agency indicated that the microbubble contrast agent Definity (perflutren lipid microsphere) is associated with the potential risk of “cardiopulmonary reactions.” However, the FDA did indicate that listing of a drug and a potential safety issue on its website “does not mean that FDA is suggesting prescribers should not prescribe the drug.”
“As a result of the investigations that the FDA conducted from January to March, the agency changed our label in May from the [black-box] label that was added in October of 2007. In May, the FDA removed several of the contraindications [added in October], and moved them into the warning sections,” Hibberd said.
The FDA held an advisory panel in June to assess the safety of Definity and other microbubble contrast agents. At that meeting, federal regulators revealed that since October, the agency had received four reports of patients dying after receiving injections of the drug Definity when used in imaging the heart.
However, Hibberd noted that at the June meeting, Lantheus and others “presented a great deal of data, which seemed to satisfy the advisory committee because there have been no further changes to the May label, subsequent to the meeting.”
“Essentially, the agency is putting out old news by issuing this list now, because it is reflective of the situation at the beginning of the year, not now,” he added. “We were surprised that agency would confuse the issues by publishing a list that would have only been relevant at the beginning of the year...there is no new news here at all.”
In commenting on Definity’s exclusivity on the FDA list, Hibberd noted that Lantheus’ only U.S. competitor, GE Healthcare’s Optison, may not have been back on the market long enough to evaluate its adverse events.
Global sales of Optison were halted in November 2005 when the good manufacturing practice matters were identified. In November 2007, the FDA approved the plant to resume production for sales in the United States.
“Hypothetically, it may be that since the other agent on the market, which was reintroduced at the end of 2007, may not have been in significant use in the clinical community. And if it’s not being used, you wouldn’t necessarily have any events occur in association,” Hibberd said.
In response, GE spokesperson, Brian McKaig, said that more than one million doses of Optison have been administered over the past 10 years with 12 serious adverse events spontaneously reported. He added that the company is not aware of any deaths or additional reports of serious non-fatal reactions caused by Optison. McKaig also pointed out that “while the two products contain the same inert perflutren gas within their microsphere structures, the Optison shell structure is based on albumin while the Definity shell is based on a lipid.”
Since October, Lantheus has taken several steps, established in collaboration with the FDA, to continue to evaluate the safety of Definity.
In May, Lantheus initiated a multicenter Phase IV observational, non-randomized CaRES (Contrast Echocardiography REgistry for Safety Surveillance) registry to evaluate the safety profile of Definity to provide safety information on the use of ultrasound contrast agents in routine clinical practice. Hibberd said that the company hopes to publish the results of CaRES either later this year, or in 2009.
Additionally, Hibberd said that they will be conducting controlled studies later this year in patients with and without pre-existing pulmonary hypertension—a patient subgroup that the