Safety rumors plague Squibb's ProHance launch

ProHance developer Bristol-Meyers Squibb has discovered that unseatingMagnevist from its position atop the MRI contrast agent marketwill not be a cake walk. Squibb conducted damage control at lastmonth's Society for Magnetic Resonance Imaging meeting to refuterumors about adverse reactions to ProHance injections.

Squibb presented patient safety data on the nonionic gadolinium-basedagent to the SMRI's safety committee at the society's meetingin San Francisco. Committee members had asked Squibb to addressseveral cases of serious adverse reactions reported since theagent's November approval by the Food and Drug Administration(SCAN 12/2/92).

Both Squibb and Omniscan distributor Sterling Winthrop havebeen taking runs at Magnevist's huge share of the MRI contrastmarket, which has accumulated over the four years that the Berlexagent was the only contrast product with FDA approval. Omniscanreceived the agency's approval in January (SCAN 1/27/93).

An FDA review in 1991 found all three agents to be equallysafe and effective. ProHance has been approved for multiple doses,while neither Magnevist nor Omniscan has FDA approval for doseshigher than the standard 0.1 mmol/kg.

Squibb anticipated that radiologists would look long and hardat ProHance's safety profile before switching from Magnevist.The fact that ProHance is nonionic had raised hopes that the agentmight be perceived as being safer than ionic Magnevist, althoughthe FDA has asked suppliers to refrain from making safety claimsbased on an agent's nonionic characteristics.

But even before Squibb had submitted its first quarterly reporton adverse drug experiences to the FDA, the grapevine of MRI userswas rife with stories describing alleged ProHance-related reactions.

"I'm concerned that there may be something going on thatwe don't know about," said Dr. Emanuel Kanal, co-chairmanof the SMRI safety committee. "I'm also concerned that theremay be nothing going on, but that the hype is such that peoplethink incorrectly that there is something going on."

As an expert in MRI safety, Kanal has fielded calls from concernedradiologists and is attempting to track down any definite incidentsinvolving serious reactions to ProHance injection. Although itis difficult to confirm retrospectively that a reaction was causedby a drug, the severity of actual events is clearly less thanthose rumored to have happened, Kanal said.

Dr. Adeoye Y. Olukotun, vice president of medical affairs forSquibb Diagnostics, described for the SMRI safety committee fourknown cases of hospitalization following ProHance injection: abrief cardiac arrest inside the magnet in a patient with 17 previouslydocumented cardiac arrests; a seizure in an elderly woman witha history of encephalitis and encephalopathy; a patient who developedhives and diaphoresis, which became more severe the day afterthe injection; and syncope in an elderly man.

MORE WORRISOME THAN THE REPORTS of serious reactions followinginjection of ProHance may be the cases of nausea and vomitingthat were documented more frequently than expected upon the product'srelease.

Squibb voluntarily withdrew 12,000 vials of ProHance from circulationin January after determining that it was the one lot primarilyresponsible for the slightly increased rates of nausea and vomitingbeing reported, Olukotun said.

"Even though the rates of those events were still withinthe limits on the package insert, we had expected the performanceof the product to be much better than it actually was," hesaid.

A chemical analysis done at the time of the withdrawal revealedno difference between the withdrawn lot and any other lots. Inretrospect, the withdrawal was probably premature and did moreto fuel the rumor mill than anything else, Olukotun said.

Most radiologists using ProHance have not experienced whatthey would consider high numbers of adverse reactions. But thosewho have are concerned.

Dr. William G. Bradley Jr., director of MRI at Long Beach MemorialMedical Center in California, said his department observed nauseaand vomiting at higher frequencies than expected in patients givenProHance injections from the first two lots they received. Similarsymptoms had also been observed in patients injected with Magnevist,but those incidents were spread over a longer period of time,Bradley said. The vials of ProHance being used at the time werereturned to Squibb in exchange for a third supply, and the reactionrate has since been lower.

"There is definitely a problem with the drug," Bradleysaid. "It may be related to the fact that the first two lotshad been sitting on a shelf for a year and a half. It appearsthat if the drug is fresh, we don't see the same kinds of reactionsto it."

Others believe that perceived problems with ProHance are simplythe result of the extra attention given to a new product. SterlingWinthrop's Omniscan has not undergone the same degree of scrutinysince its approval in January, but that may be because ProHancehad already shouldered the brunt of the market's attention.

Another point in Squibb's favor is the fact that it's difficultto make scientifically valid conclusions on adverse reactionsbased on the relatively small number of ProHance injections thathave been administered to date. Fewer than 100,000 doses of ProHancehave been administered, compared to about five million Magnevistdoses.

"If you want to compare something that's of such low incidence,you're going to need hundreds of thousands of doses at least tomake a true assessment," Kanal said. "It is, in my opinion,inappropriate science to jump to conclusions now."

The SMRI's safety committee is collecting data from all threecontrast media companies for publication in a comprehensive reviewof the safety factors involved with MRI contrast media.

Meanwhile, many radiologists have adopted a wait-and-see attitudetoward the new agents.

"Particularly since there's no significant cost differentialright now, I felt I should stick with the safety of the (agent)that I know," said Dr. Allen D. Elster, director of MRI atBowman Gray School of Medicine in Winston-Salem, NC. Elster usesMagnevist.

But no contrast agent's safety record should be cause for complacencyon the part of radiologists, he said.

"This isn't water we're injecting," Elster said."It's a drug. Reactions are going to happen."