Reckitt Benckiser will be pulling its Suboxone tablets from the market within the next six months, which effectively directs all patients on the tablets to the film product, the company advised the Food and Drug Administration (FDA) on September 25. In addition, in a “Citizens’ Petition,” Reckitt asked the FDA to consider not approving any buprenorphine products that are not in unit-dosed, child-resistant packaging.

The reason for the moves is safety, according to the company: Reckitt has been watching pediatric exposures for the past few years and received the raw data — which they paid for — from poison control centers earlier this month showing that there is an 8.5 times greater risk of accidental pediatric exposure with the tablets than with the film.

Reckitt paid for the data, which is still in raw form from RADARS (Research Abuse Diversion and Addiction-Related Surveillance), and cannot share it, Tim Baxter, M.D., Reckitt global medical director, told ADAW. It will be presented at the annual meeting of the Association for Medical Education and Research in Substance Abuse in Bethesda, Md., in November. Five children died, four of whom had taken Suboxone tablets and one of whom had taken a generic buprenorphine (without naloxone) tablet, Baxter told ADAW. Reckitt doesn’t have any details of the deaths, such as whether the children had ingested other drugs as well. There is some evidence from animal models that the “ceiling effect,” in which buprenorphine cannot cause a lethal overdose, is not present in young children, according to Reckitt. In any event, even one death is too many, said Baxter.

“We’ve been monitoring pediatric exposure since we launched in 2003,” Baxter told ADAW. Since then, the FDA, prodded by pain reliever overdose deaths, has required certain controlled substances — including Suboxone — to have a REMS (Risk Evaluation and Mitigation Strategy). Additionally, Reckitt has had in place an ongoing RiskMAP (risk minimization action plan). “As part of our RiskMAP and REMS, we’ve been gathering this data and sending quarterly reports to the FDA,” said Baxter.

In the past, the pediatric exposures to tablet and film were similar, but this year for the first time there appeared to be a “divergence,” he said. There weren’t enough data points to make a statistical analysis until June. At that point, Reckitt asked RADARS to do the analysis, and it came in on September 14 (after we interviewed Baxter for the tapering article in the September 10 issue of ADAW).

While Reckitt’s plan is to remove the tablets gradually, the FDA may ask them to do it faster, said Baxter.

Morgan Liscinsky, spokeswoman for the FDA, said the agency couldn’t comment on the issue because it hadn’t “reviewed the data leading to the sponsor’s decision.” Pharmaceutical companies (called “sponsors” in FDA parlance) are allowed to remove products voluntarily without the approval of the FDA, she said.

It’s not clear why there were more pediatric exposures with the tablet than the film, but since the main difference is the unit-dose packaging (in which each dose is separately packaged), said Baxter, that is assumed to be the reason. “We did a root cause analysis and we weren’t able to show exactly what the reason was,” he said.

From the fourth quarter of 2009 to the first quarter of 2012, there were just under 2,380 cases of accidental pediatric exposures reported by the poison control centers, said Baxter. For the tablets, there was an occurrence rate of 6.25 cases of pediatric exposure per 10,000 patients compared to .71 cases of pediatric exposure per 10,000 patients with film.

The data came from poison control centers, which report to RADARS, which prepares analyses for pharmaceutical companies who subscribe to the service.

The only differences between the film and the tablets during the period of data studied were the education campaign (started with the launch of the film just over two years ago) and the packaging. “We did give education on pediatric exposure initially as part of the REMS for the film,” said Baxter.

The treatment field has been cynical about Reckitt’s move to the film, because it’s more expensive than the tablet, and because the tablet lost patent protection three years ago. The film is patent-protected until 2023. The criticism is that Reckitt is motivated by a desire to avoid the revenue loss that would come from generic competition. So far, there is no generic on the market. The process of blending the naloxone and the buprenorphine, although it was underwritten by the federal government, belongs to Reckitt. The naloxone is needed to prevent people from injecting the buprenorphine to get high. Reckitt did have a buprenorphine-only product — Subutex — but has withdrawn it.

Last year, Reckitt told investors that efforts were being made to transfer all patients to film as part of protecting Suboxone from generic competition (see ADAW, May 30, 2011).

“I don’t agree with that perspective, because this [the move to pull tablets] is driven purely by the safety aspect,” Baxter told ADAW on September 26. In fact, Reckitt’s New Drug Application for the film stated that the unit-dose packaging would be less subject to diversion than the tablets, he said. “We didn’t think it would be this dramatic,” Baxter said.

CSAT responds

The Substance Abuse and Mental Health Services Administration (SAMHSA) has been monitoring pediatric exposures to buprenorphine via the Drug Abuse Warning Network (DAWN), which looks at emergency room “mentions” of drugs. “Pediatric exposure to any medication is of concern to us,” said Nick Reuter, with SAMHSA’s Center for Substance Abuse Treatment, which is responsible for the waiver process allowing physicians to be buprenorphine providers. In 2010, CSAT found an unusually high number of pediatric exposures to buprenorphine compared to other drugs in the class, like oxycodone, Reuter told ADAW. “We went out to make sure that the treatment providers were aware of the pediatric exposures,” he said.

Reuter seemed surprised to learn that there were deaths associated with buprenorphine. “When it comes to pediatric exposure we spend a lot more time talking about methadone, where pediatric exposures are lethal, resulting in five to six deaths a year,” he said.

DAWN data on pediatric exposures to buprenorphine found there were 560 emergency room mentions in 2008 and 1,227 in 2009. There was no data released for 2010, and Reuter seemed uncertain about whether there will be a DAWN report for 2011.

Reuter said that while the federal government supported the clinical trials leading to the commercializing of Suboxone, it was difficult to find a sponsor at the time. The view in the pharmaceutical world was that treating addicts was not profitable. That has changed, with Reckitt Benckiser reporting that Suboxone constitutes almost a quarter of its revenue. “We don’t read those,” said Reuter, referring to financial reports. “We don’t have a role in the financial part.”

But the financial part is connected to treatment, because when the medication is too expensive, payers — such as state Medicaid programs — cap its treatment at one or two years. A final rule awaiting approval in the Office of Management and Budget would allow methadone clinics to dispense Suboxone (or any buprenorphine product approved for opioid addiction treatment) without the time-in-treatment constraints required for methadone — in other words, take-homes. But the whole idea might be too costly for methadone clinics if there is no generic available.

Meanwhile, Reckitt Benckiser insists that its move has nothing to do with finances but is only related to child safety. Reckitt advises patients on the tablets to consult with their physicians about a transfer to film.

Correction

In the above article (“Reckitt pulls Suboxone, citing pediatric exposures,” ADAW October 1, 2012), the date that should have been listed for the company advising the Food and Drug Administration (FDA) of the move was September 18. The date the company learned of the poison control information was September 15. The date of the press release announcing the information was September 25 – the date we listed.