ProHance developer Bristol-Meyers Squibb has discovered that unseating
Magnevist from its position atop the MRI contrast agent market
will not be a cake walk. Squibb conducted damage control at last
month's Society for Magnetic Resonance Imaging meeting to refute
rumors about adverse reactions to ProHance injections.
Squibb presented patient safety data on the nonionic gadolinium-based
agent to the SMRI's safety committee at the society's meeting
in San Francisco. Committee members had asked Squibb to address
several cases of serious adverse reactions reported since the
agent's November approval by the Food and Drug Administration
Both Squibb and Omniscan distributor Sterling Winthrop have
been taking runs at Magnevist's huge share of the MRI contrast
market, which has accumulated over the four years that the Berlex
agent was the only contrast product with FDA approval. Omniscan
received the agency's approval in January (SCAN 1/27/93).
An FDA review in 1991 found all three agents to be equally
safe and effective. ProHance has been approved for multiple doses,
while neither Magnevist nor Omniscan has FDA approval for doses
higher than the standard 0.1 mmol/kg.
Squibb anticipated that radiologists would look long and hard
at ProHance's safety profile before switching from Magnevist.
The fact that ProHance is nonionic had raised hopes that the agent
might be perceived as being safer than ionic Magnevist, although
the FDA has asked suppliers to refrain from making safety claims
based on an agent's nonionic characteristics.
But even before Squibb had submitted its first quarterly report
on adverse drug experiences to the FDA, the grapevine of MRI users
was rife with stories describing alleged ProHance-related reactions.
"I'm concerned that there may be something going on that
we don't know about," said Dr. Emanuel Kanal, co-chairman
of the SMRI safety committee. "I'm also concerned that there
may be nothing going on, but that the hype is such that people
think incorrectly that there is something going on."
As an expert in MRI safety, Kanal has fielded calls from concerned
radiologists and is attempting to track down any definite incidents
involving serious reactions to ProHance injection. Although it
is difficult to confirm retrospectively that a reaction was caused
by a drug, the severity of actual events is clearly less than
those rumored to have happened, Kanal said.
Dr. Adeoye Y. Olukotun, vice president of medical affairs for
Squibb Diagnostics, described for the SMRI safety committee four
known cases of hospitalization following ProHance injection: a
brief cardiac arrest inside the magnet in a patient with 17 previously
documented cardiac arrests; a seizure in an elderly woman with
a history of encephalitis and encephalopathy; a patient who developed
hives and diaphoresis, which became more severe the day after
the injection; and syncope in an elderly man.
MORE WORRISOME THAN THE REPORTS of serious reactions following
injection of ProHance may be the cases of nausea and vomiting
that were documented more frequently than expected upon the product's
Squibb voluntarily withdrew 12,000 vials of ProHance from circulation
in January after determining that it was the one lot primarily
responsible for the slightly increased rates of nausea and vomiting
being reported, Olukotun said.
"Even though the rates of those events were still within
the limits on the package insert, we had expected the performance
of the product to be much better than it actually was," he
A chemical analysis done at the time of the withdrawal revealed
no difference between the withdrawn lot and any other lots. In
retrospect, the withdrawal was probably premature and did more
to fuel the rumor mill than anything else, Olukotun said.
Most radiologists using ProHance have not experienced what
they would consider high numbers of adverse reactions. But those
who have are concerned.
Dr. William G. Bradley Jr., director of MRI at Long Beach Memorial
Medical Center in California, said his department observed nausea
and vomiting at higher frequencies than expected in patients given
ProHance injections from the first two lots they received. Similar
symptoms 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 were
returned to Squibb in exchange for a third supply, and the reaction
rate has since been lower.
"There is definitely a problem with the drug," Bradley
said. "It may be related to the fact that the first two lots
had been sitting on a shelf for a year and a half. It appears
that if the drug is fresh, we don't see the same kinds of reactions
Others believe that perceived problems with ProHance are simply
the result of the extra attention given to a new product. Sterling
Winthrop's Omniscan has not undergone the same degree of scrutiny
since its approval in January, but that may be because ProHance
had already shouldered the brunt of the market's attention.
Another point in Squibb's favor is the fact that it's difficult
to make scientifically valid conclusions on adverse reactions
based on the relatively small number of ProHance injections that
have been administered to date. Fewer than 100,000 doses of ProHance
have been administered, compared to about five million Magnevist
"If you want to compare something that's of such low incidence,
you're going to need hundreds of thousands of doses at least to
make 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 three
contrast media companies for publication in a comprehensive review
of the safety factors involved with MRI contrast media.
Meanwhile, many radiologists have adopted a wait-and-see attitude
toward the new agents.
"Particularly since there's no significant cost differential
right now, I felt I should stick with the safety of the (agent)
that I know," said Dr. Allen D. Elster, director of MRI at
Bowman Gray School of Medicine in Winston-Salem, NC. Elster uses
But no contrast agent's safety record should be cause for complacency
on the part of radiologists, he said.
"This isn't water we're injecting," Elster said.
"It's a drug. Reactions are going to happen."