FDA Panel Says a Cautious 'Yes' to Buprenorphine Implant

Megan Brooks

March 21, 2013

The US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) today voted for approval of buprenorphine subdermal implant (Probuphine, Titan Pharmaceuticals, Inc) for maintenance treatment of opioid dependence.

The vote was 10 to 4 (with 1 abstaining) that the efficacy, safety, and risk-benefit data supplied by the company supports approval.

The panel "seemed to agree that this is a product with great potential utility, but there is some deficiencies in terms of dosing and REMS (Risk Evaluation and Mitigation Strategies) but that overall need for a product such as this on the market exceeded those deficiencies," said panel chair Edward Covington, MD, from the Cleveland Clinic Foundation.

Probuphine is an implantable, long-acting version of buprenorphine sublingual tablets. The implant is designed to deliver 6 months of continuous, round-the-clock, long-term therapeutic levels of buprenorphine following administration of a single subcutaneous implant in the upper arm in a 10- to 15-minute office procedure.

As previously reported by Medscape Medical News, Probuphine demonstrated increased efficacy compared with placebo and noninferiority compared with sublingual buprenorphine/naloxone in the treatment of opioid dependence in 2 phase 3 safety and efficacy trials involving more than 400 opioid-dependent adults.

Impact on Abuse, Diversion

During Thursday's PDAC meeting, FDA clinical reviewer Rachel Skeete, MD, noted that in testing, Probuphine-treated patients were more likely than placebo-treated patients to submit opioid-negative urine samples on more occasions and were less likely to require supplemental sublingual buprenorphine for treatment of symptoms of withdrawal.

However, the "vast majority of patients, even Probuphine-treated patients, persisted in illicit opioid use," she noted.

Dr. Skeete also noted that rescue medication in the form of sublingual buprenorphine was used in the trials and that it is to be used in clinical practice with Probuphine.

"The clinical trials demonstrate that the use of sublingual buprenorphine was less with Probuphine. However, the use was not eliminated, and this calls into question the impact that Probuphine will have on abuse and diversion and accidental pediatric exposure," she said.

She noted that Probuphine was given priority review status back in January on the basis of a reduced risk for abuse, diversion, overdose, and pediatric exposure compared with sublingual buprenorphine.

"There was no question that this drug does have some effect in reducing illicit opioid use, [panel members] were all in agreement with that, but there was universal disappointment about the lack of information as to the optimal dosing," said Dr. Covington.

Some Safety Concerns

FDA reviewers raised concerns about insertion and removal procedures of the implant.

Dr. Skeete said the safety profile of Probuphine subdermal implant is "similar overall" to the established safety profile of buprenorphine in sublingual formulation. "However, with this implantable formulation, there are important safety risks associated with the insertion and removal procedures, which do not appear to have been fully characterized. Furthermore, the new training and certification program, which are intended to mitigate this risk, have not yet been validated," she said.

Overall, said Dr. Covington, the consensus of the panel is that "we have a drug that has a long track record, and we have implants that have long track records, and in putting them together, the only concern is that people such as myself might be implanting them, and there are questions as to the safety of that, which remains to be determined."

Dr. Skeete said "unanswered questions" remain about management at the end of treatment and reimplantation. Jason Bunting, PharmD, risk management analyst at FDA, told the panel that there are "several concerns" with the company-proposed REMS.

The panel agreed. On the question, "Is the REMS proposed by Titan Pharmaceuticals sufficient?," the vote was 5 "yes" and 4 "no," with 6 abstaining. Dr. Covington noted that, in general, the panel had concerns about the practicality of implementation of the REMS plan, rather than the overall safety of the plan.