The History of Product Label Changes for DEFINITY® in the US

a previously unmet clinical need: at least 10–15 % of echocardiograms in the US are ‘technically difficult,’ usually because of patient-related factors, including lung disease and obesity. 21 Such examinations are usually salvaged with the administration of a UCA. This prevents downstream testing, lowers healthcare costs, and results in more timely and accurate diagnoses. 22 DEFINITY was contraindicated at product approval in two patient subsets: those with known hypersensitivity to octafluoropropane (perflutren, the constituent gas within the DEFINITY microbubble), and those with known cardiac shunts. Additionally, product labeling specifically contraindicated intra-arterial injection and use in patients with prior hypersensitivity reactions to perflutren. The contraindication in patients with shunts and the prohibition of intra-arterial injection are related to a theoretical concern regarding the potential for systemic embolization. Although the diameter of a DEFINITY microbubble ranges from 1.1 μ m to 3.3 μ m, about 2 % of these microbubbles are >10 μ m, with a maximum diameter of 20 μ m. 1 Although, under normal conditions, this small subset of microbubbles >10 μ m are filtered by the pulmonary microvasculature, larger microbubbles could access the systemic circulation in patients with intracardiac shunts (or following direct intra-arterial injection) and Abstract DEFINITY ® (Perflutren Lipid Microsphere Injectable Suspension, Lantheus Medical Imaging, North Billerica, MA) was approved by the US Food and Drug Administration in 2001 for “opacification of the left ventricular border in patients with technically difficult echocardiograms”. Since then, product labeling has been substantially revised on three occasions, initially due to safety concerns, and more recently to reflect a large body of literature which supports the excellent risk–benefit profile of this agent. This article describes in detail the substantive modifications of the product labeling for DEFINITY since 2001, and the associated supportive scientific data and public regulatory meetings.