Intravenous (IV) tramadol's benefits for severe acute pain were not greater than its potential risks, FDA advisers said Tuesday.
In a 14-8 vote, members of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and Drug Safety and Risk Management Advisory Committee said Avenue Therapeutics did not submit adequate information to support its position that the benefits of IV tramadol outweighed its risks in managing acute pain severe enough to require an opioid in an inpatient setting.
Tramadol, a schedule IV opioid analgesic, is approved in (Ultram). The drug binds to opioid receptors and inhibits serotonin and norepinephrine reuptake. Intravenous tramadol is used in Europe; if approved, Avenue's product will be the first injectable form in the U.S.
The advisory committee meeting marked Avenue's third attempt at FDA approval. The company submitted new drug applications in and ; both were turned down due to safety concerns.
After its last rejection, Avenue submitted a formal dispute resolution request. In response, the FDA asked for additional input from an outside panel before making a decision.
At the meeting, Lisa Wiltrout, MD, of the FDA's Office of New Drugs, summed up the FDA's position: "Tramadol IV's delayed onset of analgesia, combined with its inability to be titrated to effect, leads to a serious safety concern of additive opioid-related adverse events from use of opioids in succession, also referred to as opioid stacking." This raises potential risks of sedation and respiratory depression, she noted.
A schedule IV opioid has less abuse liability than a schedule II or III opioid, Wiltrout acknowledged. But "no robust conclusions can be made with respect to whether intravenous use of tramadol in a medically supervised setting will confer a public health benefit," she added.
Avenue provided efficacy data from two placebo-controlled phase III studies in post-surgical adults with acute pain: one in people who had bunionectomy, the other in people who had abdominoplasty. The only rescue medication allowed in the trials was oral ibuprofen 400 mg every 4 hours as needed.
The two studies showed statistically significant differences between IV tramadol 50 mg and placebo on the primary endpoint of pain intensity. Using the two-stopwatch method, both studies also demonstrated that IV tramadol had a delayed onset of analgesia, "likely beyond 2 hours," Wiltrout noted. This delayed onset "does not support its benefit as a monotherapy to treat patients in acute pain," she added.
"The data for the efficacy was there," said advisory committee member Maryam Jowza, MD, of the University of North Carolina at Chapel Hill. "With respect to the risk, it was largely related to opioid stacking, and that's something that can be mitigated with proper use and education."
But other panelists saw Avenue's data differently. "The delayed onset and the unpredictable pharmacokinetics of this drug, coupled with the inability to titrate the drug, make this quite a problematic formulation," said Brian Bateman, MD, MSc, of Stanford University School of Medicine in California. "I think we need trials that better reflect the type of setting where this drug would be administered, where opioids would be able to be used for continued pain or breakthrough pain," he added.
"There's no compelling evidence presented that there's less abuse liability with this formulation compared to schedule II opioids," Bateman pointed out. "We really have no data to suggest that the use of inpatient IV opioids and the differences between them could impact long-term misuse, abuse, or the development of opioid use disorder."
The advisory committee meeting took place less than a week after the on recommendations and expedited programs for companies developing non-opioid analgesics for acute pain, a move to encourage more nonaddictive pain management options.
"Given the current opioid crisis in the U.S., we should have strong evidence that this new opioid would provide benefits over what's currently available, and I didn't see that evidence," said panelist Marie Griffin, MD, MPH, of Vanderbilt University in Nashville, Tennessee.
"We should also have strong evidence that there would not be unintended consequences that would actually be harmful," Griffin added.
FDA advisory committees provide the agency with non-binding recommendations. Avenue expects the FDA to respond to its appeal of the advisory committee meeting.