“Opioid Stacking” Concerns Lead FDA to Reject Avenue Therapeutics Drug

An opioid that Avenue Therapeutics reformulated for treating post-surgical pain in hospital settings has been rejected by the FDA due to safety concerns.

The Avenue (NASDAQ: [[ticker:ATXI]]) drug is an intravenous formulation of tramadol, an opioid that first reached the US market 25 years ago in pill form. Now New York-based Avenue is trying to offer an alternative to painkillers used after surgical procedures, as well as an improvement over an intravenous formulation of tramadol that is already approved for use in Europe. But that improvement may have unwittingly led to the basis for the FDA rejection.

In Europe, intravenous tramadol is given over two to three minutes. Rapid administration of the drug can lead to adverse effects such as nausea and dizziness, and less commonly, heart rhythm problems. Avenue has patented a method for dosing intravenous tramadol over a period ranging from 10 minutes to about 45 minutes, which the company says may improve its side effect profile compared to the version used in Europe.

According to Avenue, the FDA’s letter said that a patient requiring pain relief between the first dose of Avenue’s version of intravenous tramadol and the onset of its effects would need another rescue medicine. The likely choice would be another opioid, resulting in “opioid stacking,” which the FDA said would increase the likelihood of opioid-related adverse effects.

Avenue said that the agency acknowledged that the drug met the goals of Phase 3 testing and other than the concerns about drug stacking, no safety problems were raised. The FDA said it also requires validation of the company’s sterilization procedures, which the company says is planned for later this quarter. In a prepared statement, Avenue President and CEO Lucy Lu said that the company believes its data supports the use of its drug as an alternative to conventional opioids. She added that the company will request a meeting with the FDA to discuss the regulatory decision.

Shares of Avenue opened Monday at $5.19, down more than 52 percent from Friday’s closing price.

Among opioid drugs, tramadol is regarded as one of the safer ones because it causes fewer side effects. Avenue notes in its regulatory filings that the drug doesn’t cause as much respiratory depression compared to other opioids, nor does it impair blood flow or immune system function. The company also says tramadol causes fewer gastrointestinal problems, such as constipation. Though the drug is an opioid, the US Drug Enforcement Administration classifies it as a Schedule IV controlled substance, which is a lower category for potential abuse compared to the Schedule II classification of most opioids.

Tramadol was first approved in 1995 under a regulatory submission by Janssen Pharmaceuticals, now a Johnson & Johnson (NYSE: [[ticker:JNJ]]) subsidiary, which markets the tablet under the name Ultram. Another J&J division markets a pill version of the drug called Ultracet, which is a combination of tramadol and acetaminophen.

Avenue formed in 2015 as a subsidiary of Fortress Biotech (NASDAQ: [[ticker:FBIO]]). It spun out of Fortress in 2017, raising $33 million in its IPO.

Image: iStock/Amornrat Phuchom