The Food and Drug Administration (FDA) dealt Reckitt Benckiser Pharmaceuticals three setbacks in a single February 22 letter: (1) it denied the manufacturer’s request that all generic competition to Suboxone (buprenorphine plus naloxone) be designed to limit pediatric exposure, (2) it approved two generic competitors and (3) it asked the Federal Trade Commission (FTC) to investigate the company for anticompetitive practices related to its efforts to protect its patent on the buprenorphine-naloxone medication.

Last September, Reckitt wrote the FDA that it intended to voluntarily stop distributing Suboxone tablets because of the risk of pediatric exposure — a move the substance abuse treatment field saw as a cynical attempt to safeguard the company’s patent protection on the film (see ADAW, October 1). At the same time, and in what treatment providers saw as in the same vein, Reckitt asked the FDA to impose the same pediatric safety restrictions on any other similar medications — in other words, on any generics that might be coming along.

The company had already tried to transition all patients from tablet to film, as the patent expired on the tablet in October 2009 and the film is patented until 2023; the company was worried about generic competition (see ADAW, May 30, 2011).

Questionable pediatric exposures

The FDA, in its February 22 letter, took all of this into account. While the Reckitt petition from last September asserts that the unit-dose packaging of the film resulted in a reduction in pediatric exposure compared to the tablets packaged in bottles, the FDA said there was no proof of this. Also, the data came from RADARS and was paid for by Reckitt.

“FDA reviewed several additional data sources in an attempt to substantiate the Petition’s claims,” said the letter, but it was not able to. There has been a downward decline in pediatric exposure to buprenorphine products, but there was no proof that this was caused by the introduction of unit-dose Suboxone film into the market.

Rather, the FDA wrote that risk evaluation and mitigation strategies (REMS) it has required on buprenorphine’s risks have helped to produce the downward trend in pediatric exposures and other problems by “reducing the prevalence in the addiction treatment community of the notion that buprenorphine products are not dangerous in overdose or subject to abuse.” All generic buprenorphine products will have to have the same REMS, the FDA letter noted. The REMS also adequately address pediatric exposure, so that the unit-dose childproof packaging should not be required, the FDA said in denying the Reckitt petition. The FDA also noted that many drugs that are harmful to children are sold in bottle, not unit-dose, form.

Tablets can stay

Also, the FDA said that Reckitt had not, in fact, stopped selling the tablets as it said it would. Therefore, that could not be used as justification not to approve the generics. And the FDA said that there was no reason to withdraw the tablets for reasons of safety.

The FDA also chastised Reckitt for continuing to market the tablets even though they had the data on pediatric exposure — including the first report of a pediatric death — for two years after those reports came in, saying the company’s actions “undermine, to some extent, its claims with respect to the severity of this safety issue.”

And with biting understatement, the FDA suggested that Reckitt’s move was based only on financial interests. “The timing of Reckitt’s September 2012 announcement that it would discontinue marketing of the tablet product because of pediatric exposure issues, given its close alignment with the period in which generic competition for this product was expected to begin, cannot be ignored,” the FDA said.

So the FDA referred the matter to the FTC, “which has the administrative tools and the expertise to investigate and address anticompetitive business practices.”

In a February 25 press release, Reckitt said it was “disappointed” with the FDA’s decision, but it would “continue to work with the FDA on safety enhancements” and will “carry on with the decision to discontinue the sale of its loose tablet bottles” of Suboxone in the United States.

The company did not return a request for a comment. The press release came from the United Kingdom headquarters and not from the Richmond, Virginia, headquarters where medical director Tim Baxter, M.D., interviewed by ADAW last fall, is located and where the FDA sent the letter.

Treatment field gratified

Treatment advocates were gratified by the decision, cheering on the FDA for “doing the right thing” in comments posted on the Internet.

Jeffrey T. Junig, M.D., Ph.D., a psychiatrist who wrote a scathing letter to the editor saying “Shame on them” to Reckitt (see ADAW, October 8, 2012) and has posted frequently on his own blog about Reckitt’s attempts to thwart generics, told ADAW that “many doctors in the field have suspected that the film was introduced not to meet patient needs as much as to survive generic competition.” Because Reckitt has convinced payers that the film is less subject to abuse, payers are in many cases covering only the film, which is more expensive than the tablet — and, of course, much more expensive than the generics.

“This is maddening in an era of limited resources,” said Junig, who is a psychiatrist with the University of Wisconsin Oshkosh Student Health Service and assistant clinical professor of psychiatry at the Medical College of Wisconsin. “The referral to the FTC was a surprising blow to their marketing strategy, and is a sign that the FDA understands the severity of the problem of opioid dependence.”

Generics

The approval of the generics was “very good news for patients taking buprenorphine,” said Junig. “Many patients lose insurance coverage as part of the fallout of their addiction, and the high price of Suboxone has encouraged improper use of the medication, such as using small pieces of one dose for many days, rather than taking a sufficient dose,” he said. “Hopefully price competition will result in greater access to allow for appropriate dosing.”

It’s easy to interchange between film and tablet, said Junig. “The transition is a no-brainer,” he told ADAW. “The film and the tab have the same ingredients, and each dissolves in the mouth to yield the exact same mix of molecules, which are then absorbed through the oral mucosa and into the bloodstream.”

It’s also simple to transfer from Suboxone to generic buprenorphine-naloxone, he said.

Both the film and the tablet must be allowed to dissolve under the tongue and be absorbed that way. If swallowed instead of taken sublingually, the buprenorphine is metabolized by the liver during the “first pass” and never gets into the circulation.

The approval of the generics — the sponsors are Actavis and Amneal — is also significant because of the greatly increased demand that is expected for buprenorphine, now that opioid treatment programs can dispense take-homes without a long waiting period (see ADAW, December 10, 2012, December 17, 2012).