GAITHERSBURG, Md. - Intravenous phenytoin should continue to be marketed but with revisions to its label that include more information about the risk of "purple glove syndrome" associated with its use, advisors to the Food and Drug Administration recommended on Nov. 3.
At a joint meeting of the FDA's Peripheral and Central Nervous System Drugs and the Drug Safety and Risk Management Advisory committees, panelists reviewed the available evidence on the risk of purple glove syndrome (PGS) associated with the use of IV phenytoin, which was approved in 1956.
IV phenytoin has been associated with PGS, a local reaction that can start within hours of the infusion with edema and purple discoloration around the infusion site. This edema and discoloration can progress but usually resolves within days to weeks. However, in some cases, it leads to necrosis of the skin, ischemia, and in rare cases, amputation.
Since a pro-drug of phenytoin – IV fosphenytoin – was approved in 1996 and is now being used more often than IV phenytoin, the risk of PGS associated with the drug has become a larger issue. The current uses of the two drugs include the treatment of status epilepticus and the prevention and treatment of seizures during neurosurgery.
Most of the panel members agreed that IV phenytoin treatment was associated with PGS. Several panelists said that although the incidence of PGS associated with IV phenytoin was not clear, it is probably uncommon. The panel members voted 18 to 11 that there was not enough evidence to conclude that IV fosphenytoin causes PGS. However, most of those voting no said that a link was possible and that the incidence was likely much less common and less severe than with IV phenytoin.
The panel members unanimously agreed that more regulatory action regarding IV fosphenytoin was needed, including additional dosing information, because its current label is confusing and has resulted in medication errors.
An issue that was raised by some panel members was the current shortage of IV fosphenytoin, despite the availability of generic formulations. Pfizer Inc., which markets the brand version of the drug as Cerebyx, stopped marketing it in the United States because of problems finding a U.S. manufacturer. The company continues to market Cerebyx outside of the United States, according to Pfizer representatives at the meeting.
FDA reviewers identified 11 reports of PGS in the literature in patients aged 6 months to 86 years that were associated with IV phenytoin. PGS resolved in most cases except for one that ended in amputation of the affected extremity. The incidence of PGS associated with IV phenytoin treatment in the literature ranges from 0% to 6%, mostly resulting in outcomes that are not considered serious, according to the FDA.
The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of conflicts of interest related to the topic of the meeting.