OPTISON (FS069), an ultrasonic diagnostic contrast agent, is a suspension of perfluoropropane (PFP)-filled album in microspheres of 2.0-4.5 microns average diameter and 5.0-8.O x 108 microspheresl ml. The following non clinical safety assessment studies in support of product regulatory submissions were conducted: genetic toxicology, single dose (rat, dog, monkey) and repeated (rat, dog) dose toxicology studies, hemodynamics, rabbit irritation, and in vitro blood compatibility. Dosages used throughout the studies were: 0.25, 5.0, 10, 20, or 25 ml/kg. OPTISON was nongenotoxic and nonirritant, and was compatible with human blood. It did not elicit adverse effects in single-dose studies at dosages of up to (and including) 20 ml/ kg. Initial studies conducted in rats and dogs with OPTISON repeated administration, 3 times per week for 3 weeks, showed no adverse effects in dogs to 20 ml/ kg and rats to 5 ml/kg. Mortality and adverse effects were noted in rats at dosages of 20 and 10 ml/ kg and were associated with acute pulmonary congestion. Subsequent repeated administrations for 29 and 31 consecutive days in rats and dogs, respectively, at 10 ml/kg, were not associated with adverse events, except for those which resulted from the anticipated immunogenic response to the IV administration of OPTISON human albumin-based microspheres. No changes in hemodynamic parameters attributable to OPTISON were reported at a dosage of 0.25 ml/ kg in dogs. It is, therefore, concluded that the intravenous administration of OPTISON, at dosages and dose regimens used in these studies, provides a large safety margin for the clinical efficacious dose for diagnostic ultrasound imaging.
Science underpinning the safety case of deep geological repositories − challenges in the past and in the future and how to maintain knowledge and competence during operation
