By DON LONG
Medical Device Daily Executive Editor
And AMANDA PEDERSEN
Medical Device Daily

In apparent response to reports of deaths associated with injections of dermal fillers, the FDA on Friday said it is reviewing two of these products: Botox, made by Allergan (Irvine, California), and Myobloc made by Solstice Neurosciences (Malvern, Pennsylvania).

Disclosure of the investigation concerning the products comes a few days after the consumer advocacy group Public Citizen (Washington) filed a petition with regulators calling for stricter warnings on Botox and Myobloc (Medical Device Daily, Jan 28, 2009).

The group said it knew of 180 reports of harmful side effects, including 16 deaths, and that these had been reported to the FDA from November 1997 to December 2006. Four of the deaths occurred in people under age 18, Public Citizen said.

In a Friday afternoon agency conference call, Russell Katz, director of the Division of Neurology Products for the FDA’s Center for Drug Evaluation and Research, said, “Most of the cases we are concerned about, and are serious, are pediatric patients who receive injections to treat spasticity.”

He said that such cases are considered off-label uses because these drugs are not approved as therapies for children under age 12. But he then went on to say that this “doesn’t mean that such use is inappropriate.”

“We are continuing to evaluate these reports,” he said, “We have asked the manufacturers to submit their comprehensive review of their databases ... we’re trying to get a better handle on these details.”

Reporters during the briefing call wanted to know the total number of adverse events, but Katz was ”reluctant to describe specific numbers” because he said those numbers vary. He did characterize the total incidents as “a relative handful” while also acknowledging that there have been some hospitalizations and at least one death related the use of the fillers.

Asked if the FDA’s investigation came in response to Public Citizen’s petition, Katz said this was not the case, that the agency had been “working on this for a while” before that submission, adding, “of course we are reviewing that and trying to see how all this fits together.”

Katz said that in terms of adverse events from cosmetic uses of the drugs, these cases were “a very few.” “The doses used in cosmetic use are usually much smaller and that’s not a big part of what we’re seeing here.”

Katz emphasized that there is “no evidence” that the adverse events are related to the drug itself. Throughout the call, he described the adverse events as more likely to be “distant effects” – essentially the spread of botulism – from the place where it is injected to a more distant site.

Botulinum toxin is one of the key ingredients of the products.

“We put this information out there for people to make their own best judgment about this,” Katz said. “I think people should be aware that there is a potential for this to happen ... . [I]f somebody does use it cosmetically and they subsequently develop symptoms that might be related to this distant spread, than both patients and physicians should take this seriously.”

Botox is Allergan’s most profitable product, with $1.2 billion in sales in 2007. Besides its cosmetic uses, it is used in certain neurological applications.

He said also that the reported reactions “may be related to overdosing” rather the result of any product defect.
Both Botox and Myobloc come with prescribing literature that warns of the risk of breathing and swelling difficulties in patients with neuromuscular disorders.

Katz said that the labeling for the products “doesn’t really describe cases of the sort which we believe we have; that’s why we are looking at changing the labeling.”

While a “black box” warning is a possibility, Katz said the agency is “considering every option,” and that it’s too premature to identify what the labeling change might be.

Katz said the adverse events were seen in cases where a wide range of dosing was used. He declined to comment on the dosages used in children with cerebral palsy since that is an off-label use, and FDA does not recommend any kind of dosage for that population.

A spokesperson for Allergan said the company is working with the FDA and providing access to its data concerning the product, but she said that no “causality” between the product and the injuries had been shown.

Solstice issued a statement attempting to underline the safety of Myobloc (Botulinum Toxin Type B), and it highlighted its efforts to educate and train physicians “in a number of ways regarding the proper use of this product as outlined in the prescribing information.”

It emphasized that the FDA’s communication “does not mean that FDA has concluded there is a causal relationship between the drug products and the emerging safety issue.”

Lawrence Biegelsen, an analyst for Wachovia, issued a note downplaying the impact of the FDA’s review, saying that it “only introduces headline risk, which we think should be contained.” He added: “Botox has a 17-year history of use in the U.S. and is often used only as a therapeutic treatment when previous treatments fail, so we do not believe Botox is used indiscriminately, nor do we believe this news will change prescribing patterns for Botox.”

Botox is approved in about 60 countries to treat limb spasms in children with cerebral palsy, and it is reported that it is used for that purpose by some doctors in the U.S.

Allergan’s spokesperson said that the company does no marketing for these applications in the U.S.

The FDA said that while it completes its review, it urges doctors to understand the potencies of Botox and Myobloc and help patients look for side effects for as long as several weeks after treatment.