Late last month, Reckitt Benckiser created a stir by unexpectedly announcing that its Suboxone tablet for treating opioid dependence will be withdrawn from the US market sometime over the next six months. The reason? The drugmaker, which is based in the UK and actually best known for household cleaning products, expressed concern that children could be accidentally harmed by easy access to tablets that are marketed in bottles.
In making its case, Reckitt cited specially commissioned data showing "consistently and significantly higher rates of accidental unsupervised pediatric exposure" with Suboxone tablets than with Suboxone Film, a newer version of its drug that dissolves under the tongue and can only be accessed by tearing open individual blister packaging. Specifically, the rates for Suboxone tablets were roughly eight times greater (read here).
"Reckitt Benckiser Pharmaceuticals has a moral obligation to act as quickly as possible on safety data relating to its products," a spokesman wrote us, noting that a risk management strategy, which included patient education, was in place since 2003 in an effort to minimize accidental exposure to children. But data indicated a rising rate of pediatric exposure in recent years, at least until the film version was introduced in 2010 (see the chart).
"...Based on the safety and public health issues raised by the recent findings and the availability of treatment advancements in the United States that have shown reduced pediatric exposure, such as Suboxone Film, Reckitt Benckiser Pharmaceuticals believed it would be unethical to continue supply of Suboxone Tablets and therefore informed the FDA of its decision," he continued.
The very same day, though, Reckitt also filed a Citizen's Petition with the FDA, asking the agency not to approve any generic versions of Suboxone tablets unless the manufacturers implemented "national public health safeguards involving pediatric exposure educational campaigns and child-resistant, unit-dosed packaging to reduce the risk of pediatric exposure" (look here and here).
To generic drug makers, some physicians and Wall Street analysts, however, the moves amounted to a transparent one-two punch designed to delay lower-cost generic tablets from reaching the market. The patent on Suboxone tablets, in fact, expired two years ago, while patent on Suboxone Film expires in 2022, according to the Reckitt spokesman. "If Reckitt is so concerned about safety," says one industry source, who asked not to be named, "then why not take the tablets off the market right away? Their tablets are still on the market without blister packing, which they themselves say is unsafe."
Meanwhile, Reckitt has gradually raised the price of Suboxone Tablets in order to switch patients. The current wholesale average cost (WAC) for a bottle of 30 Suboxone Tablets is $161.70 for the 2 mg dose and $289.80 for the 8 mg dose, according to the Reckitt spokesman. In July, however, the same bottle of the 2 mg dose cost $140.00 and the 8 mg WAC was $252.00, industry sources say. Meanwhile, Suboxone film pricing has held steady: WAC pricing for a carton of 30 Suboxone Film strips remains $117.85 for the 2 mg dose and $211.15 for the 8 mg dose.
More recently, sales of Suboxone tablets fell 19 percent between August 2011 and August 2012, to $658.5 million, according to IMS Health, while sales of Suboxone film doubled to more than $764 million during the same period. "They are (removing the tablets) because generics are expected in 2013 on the tablet," says Sanford Bernstein analyst Ronny Gal. "The critical question is whether their argument that film is always safer for children will convince FDA not to approve any oral solid generic."
For these reasons, the back-to-back announcements have been met with outrage. "They have known for years that a generic tablet could destroy their golden calf — and Suboxone is Reckitt Benckiser, from an earnings standpoint. If they do not destroy the tablet, it destroys them," Jeff Junig, a psychiatrist at the University of Wisconsin Oshkosh Student Health Service and an assistant clinical professor of Psychiatry at the Medical College of Wisconsin, wrote in a letter to Alcoholism & Drug Abuse Weekly.
"I’m sure I sound... paranoid? Cynical?," wrote Junig, who also authors a blog about Suboxone. "But it is so frustrating when you see marketing trump science. This will discourage generics from making buprenorphine, which will keep the price high, which will cause deaths. Shame on them." Buprenorphine is one of two active ingredients in the Suboxone medicines; the other is naloxone. About 20 percent of profits are reportedly derived from pharmaceuticals, although this is dwarfed by household products.
"Doctors are questioning Reckitt's motives, because there are tons of kids who die from ingesting other narcotics, including methadone, and these aren't required to be (packaged) in film or are in film," says Alison Knopf, editor at Alcoholism & Drug Abuse Weekly, which is read by policymakers, addiction treatment specialists and government agencies. "They think eliminating generic competition is the real reason this is being done and they're concerned because they know there's demand for a less expensive medication" than the film.
For more than a year, in fact, several generic drugmakers have sought FDA approval to sell Suboxone tablets, including Watson Pharmaceuticals (WPI) and Teva Pharmaceuticals (TEVA), according to Gal. But Reckitt has, so far, successfully frustrated the threat of generic competition, according to industry sources. To obtain FDA approval for their drugs, the handful of generic drugmakers were told by the agency to work with Reckitt on developing a class-wide Risk Evaluation and Management Strategy, or REMS, for tablets.
"Because there are numerous NDA and ANDA products in the buprenorphine class, in the interest of public health and to reduce the burden on the healthcare system of multiple unique REMS programs, we have determined that a single, shared system to implement these REMS programs is needed. You must contact the sponsor of the reference listed drug for your ANDA, Reckitt Benckiser Pharmaceuticals Inc., regarding the development of the single shared system," the FDA wrote to generic drugmakers last year (here is the excerpt).
For months, though, this effort has stalled, according to industry sources, who tell us Reckitt has not given any indication that it will cooperate in designing such a REMS and has not shared some of the specifics with the generic drugmakers. "There are many components in their REMS, and these can be very stringent, but Reckitt won't tell us what they are. They've seized upon this and used the situation to their advantage. And no progress has been made," says a source.
The Reckitt spokesman, however, denies this. The drugmaker "has been diligently participating in discussions with both the FDA and other constituents on the development and structure of a joint REMS program to address the risks associated with the misuse, abuse and pediatric exposure of buprenorphine products for the treatment of opioid dependence. While the company cannot discuss specific details about the program, Reckitt Benckiser Pharmaceuticals has been actively engaged in these multiparty discussions," he wrote us.
Nonetheless, a single, classwide REMS has yet to emerge. And by filing the Citizen Petition last month, Reckitt will likely delay generic competition for several months more. Why? The FDA can take up to 180 days to respond. Between the lack of a unified REMS and the agency obligation to review the citizen petition, generic rivals will likely remain on the sidelines. Meanwhlie, Reckitt will continue to sell both versions of Suboxone.
At the same time, questions have also been raised about Reckitt's willingness to design blister packaging for Suboxone tablets. Experts say blister packaging is preferable to bottles. "Child resistant caps on pill bottles help, they are a deterrent, but are far from perfect," says Rick Dart, director of the Rocky Mountain Poison and Drug Center and executive director of the RADAR System, which Reckitt retained to analyze Suboxone safety data. "There are other ways of making products resistant to children... Blister packs are one way."
Reckitt actually sells the tablets in blister packaging in other countries, such as Canada (see page 22 of the monograph) and the UK. Critics say the drugmaker should have been able to do the same in the US and note that the company has acknowledged pursuing such packaging, but a Reckitt spokesman maintains there were several reasons this was not pursused, including a different formulation in the US.
"Any changes to the packaging would require a new submission with supporting data to the FDA and would take an extended period of time," he writes us, adding that Reckitt tried to package the Suboxone Tablets into blister packs and "faced many challenges, including stability. With the development of Suboxone Film, the company was able to introduce child resistant, unit-dose packaging with the same active ingredient before it was able to identify and resolve the packaging issues experienced with Suboxone Tablets."
In a footnote in the citizen’s petition, Reckitt also stated the company did not develop unit-dose packaging for their Suboxone tablets due to “technical issues involving the integrity of the tablet when attempting to remove it from the packaging.”, and that “later studies revealed that unit-dose packaging of Suboxone may be feasible” but “RBP focused its resources on the development of Suboxone Film" (this is footnote 57 on page 22.)
To Junig, the debate over packaging is a side show. "If it is impossible to produce the tabs in unit-dose form, they are essentially blocking generics if unit-dosing is required, since only (Reckitt) can make the film," he writes us. "And if they can convince the FDA that they pulled the tab for safety reasons, that kills any new application for generic Suboxone. If they just stopped making the tab for any other reason, they would lose that ‘protection.’ It's pretty tricky."