FDA delays agent reformulation in U.S.

Schering is marketing a formulation of its Magnevist gadolinium-DTPAmagnetic resonance imaging agent in Europe that is different fromthe version sold in the U.S.

While the U.S. product remains unchanged from the drug thatreceived Food and Drug Administration approval in 1988 (SCAN 6/22/88),the European version has been modified in an attempt to eliminatetransient side-effects. Side-effects have been observed with theoriginal formulation when administered in doses higher than thestandard 0.1 mmol/kg of body weight.

"We still use the old formulation in the U.S. becausethe FDA is quite slow," said Dr. Hans-Joachim Weinmann, directorof MR contrast media research for Schering AG. "In the nextcouple of months or maybe by the end of this year, the new formulationmay also be used in the U.S. and this will no longer be an issue."

Schering submitted the content of the new formulation to theFDA about a year ago, Weinmann said.

The side-effects associated with the old formulation are slighttransient increases in several laboratory blood values, specificallyserum iron and bilirubin, he said. The effect is not observedin animals.

"Only man shows these transient increases," Weinmannsaid. "We checked the whole zoo of animals."

The cause of the effect is not well understood. While no onereally knows what the mechanism is, it is generally agreed thatthe effect is minor and of no medical significance, Weinmann said.The effect is only seen with a rigorous experimental protocolbecause it is easily masked by the normal daily fluctuations inserum iron and bilirubin, he said.

Similar elevations in blood laboratory values have apparentlyalso been observed with Salutar's Gd-DTPA-BMA but not with Squibb'sGd-HP-DO3A. The effect may have nothing to do the specific chemicalsinvolved, however. Studies performed by Schering researchers havedocumented that the effect can also occur subsequent to iodinatedcontrast injections.

"Iodinated contrast agents sometimes show the same thingand nobody worries about that," Weinmann said.

The phenomenon apparently involves blood hemolysis secondaryto osmotic disturbance, according to most expert opinion. Releaseof gadolinium ions from their chelate carriers may also be ofconcern.

Schering's European reformulation involves changing the qualityof the free DTPA ligand present in Magnevist so that it is of"higher purity," Weinmann said. The reformulation hasallowed the Germans to perform clinical trials with Gd-DTPA atdoses up to 0.3 mmol/kg.