FDA Opioid Analgesics Risk Management Models Include Stadol NS, Actiq

An FDA advisory committee will consider whether risk management models used for Bristol-Myers Squibb's Stadol NS, Sanofi-Synthelab's Talwin NX and Cephalon's Actiq should be more generally applied to other opioid analgesics.

FDA is asking the Anesthetic & Life Support Drugs Advisory Committee to "comment on what measures might be appropriate to consider in the development of an overall risk management strategy that could reduce abuse and diversion without restricting access to drugs by patients in need of treatment."

"FDA would like to hear an open and frank discussion of how the potential risks associated with these products could be managed in a way that will insure adequate patient care," Anesthetic, Critical Care & Addiction Drug Products Division Director Cynthia McCormick, MD, explained in briefing materials prepared for the advisory committee.

The meeting was scheduled for Sept. 13-14, but was postponed due to the terrorist attacks in New York City and Washington D.C. (¹ (Also see "Cancer Clinical Benefit Tool Needed For Local Therapies -IntraDose Cmte" - Pink Sheet, 24 Sep, 2001.)).

FDA scheduled the meeting at a time of heightened public attention to prescription drug abuse, misuse and diversion, particularly concerning Purdue Pharma's opioid analgesic OxyContin (oxycodone).

In July, Purdue announced a series of steps - including a new black box warning - intended to address reports of abuse and diversion of OxyContin. The company was expected to make a presentation during the advisory committee meeting ('The Pink Sheet" July 30, p. 8).

The briefing materials for the meeting suggest that FDA wanted advice on whether it should routinely request more significant restrictions on distribution and promotion of opiates.

The agency outlined examples for the committee to consider, apparently based on its experience with Stadol (butorphanol tartrate), Talwin (pentazocine) and Actiq (transmucosal fentanyl).

One example cited by the agency (apparently Stadol NS, referred to in the briefing materials as "Drug A") focuses on a nasal formulation of an opioid. The parenteral formulation of butorphanol was not scheduled when it was approved in the 1970s. Bristol's nasal spray formulation was approved in 1991 after FDA's Drug Abuse Advisory Committee recommended that the agency require postmarketing surveillance rather than schedule the product.

FDA notes that there were "reports of an emerging abuse problem following availability of the nasal spray," which prompted the agency to initiate a survey. Based on those findings, "the agency underwent negotiations with the sponsor," and the nasal spray was designated a Schedule IV controlled substance in 1997.

"Following the scheduling of Drug A nasal spray, the number of abuse-related reports began to decrease, with fewer than 10 in each of the years 1998-2000," FDA said. "The number of prescriptions remained nearly stable...at approximately 1 mil."

Prescriptions peaked at 1.5 mil. per year in 1995, FDA noted, and abuse reports reached a high of 150 in 1996 and 1997.

The second example ("Drug B," apparently Talwin) relates to the reformulation of an opioid agent to discourage abuse. Talwin (pentazocine) was approved in 1969. "An increasing frequency of cases of abuse, diversion, overdose and death, including intravenous abuse of crushed tablets, were reported to the agency through the late 1970s," FDA noted. The drug was added to Schedule IV in 1979, but reports continued, FDA said.

"At the request of the agency, the product was reformulated with naloxone in 1982 and the original Drug B tablet was withdrawn from the U.S. market in 1983," FDA noted. "Reports of abuse declined dramatically following the withdrawal of Drug B, while the use of reformulated Drug B with naloxone remained stable." Purdue is developing an abuse-resistant opioid analgesic similar to that of Talwin NX.

The final example ("Drug C," apparently Actiq) relates to the development of a new formulation of a Schedule II agent. Actiq is a transmucosal formulation of fentanyl, developed by Anesta, which merged with Cephalon in 2000.

FDA asked Anesta to implement a risk management plan prior to approval. The program focuses on limiting prescriptions to patients with indication-specified diagnosis, restricted detailing programs and proper storage. "Reports of abuse, misuse or diversion of this product have been rare," FDA said.