FDA Once Again Rejects Avenue Therapeutics’ NDA for IV Non-Opioid Painkiller Tramadol

Tramadol rejected. 

According to details from a Complete Response Letter (CRL)  released this morning, the U.S. Food and Drug Administration (FDA) has again declined Avenue Therapeutics’ request to approve the intravenous non-opioid painkiller tramadol.

After releasing details of the CRL regarding the New Drug Application (NDA), the company’s shares plunged approximately 5% lower in premarket trading. 

In the new CRL, the FDA stated the unpredictable and delayed analgesia onset with the intravenous therapy could not support a benefit when given alone to manage acute pain. Additionally, the FDA said in the CRL that there is insufficient data to date to support the safety and efficacy of intravenous tramadol with other pain-relieving medications in the intended approved population. There were no Chemistry, Manufacturing and Controls issues outlined in the CRL.

In a statement released by Avenue Therapeutics, the company says it “disagrees with the FDA's interpretation of the data in the NDA and intends to continue to pursue regulatory approval for intravenous tramadol.”

This is the second CRL sent by the FDA to Avenue Therapeutics responding to the company’s wish to approve intravenous tramadol. The company resubmitted the NDA in April of this year.

Reasons Behind the Rejections of Tramadol

The FDA rejected the company’s first NDA for the intravenous therapy, citing safety concerns in the agency’s initial CRL. The agency said it was concerned that patients had to use an opioid alongside tramadol if they required an analgesic between the first dose of tramadol and analgesia onset.

“We believe that our extensive clinical database strongly supports the value of treatment with intravenous tramadol as an effective alternative to intravenous Schedule II conventional opioids,” said Lucy Lu, MD, Avenue Therapeutics’ President and Chief Executive Officer, in a statement.

The NDA was submitted on behalf of the company back in December 2019 along with positive findings from two Phase III studies. These pivotal trials evaluated intravenous tramadol in patients after bunionectomy and abdominoplasty surgeries, in addition to an open-label safety study with over 500 patients who received the therapy at 50 mg.

Additionally, the original NDA submission included data from an epidemiology study on tramadol abuse in the U.S and some countries in Europe. In this study, researchers found tramadol abuse reports were infrequent, both in their absolute number and relative to other opioid medications. In addition, the investigators reported that tramadol abuse via inaction was generally uncommon compared with oral tramadol in some countries where this therapy is available.

Real-world data, published in December in Drug and Alcohol Dependence, compared misuse and abuse of the therapy with codeine, morphine, and oxycodone. “The goal of the study is to better understand the misuse and abuse of tramadol in countries where parenteral tramadol is available, which requires consistent measures of misuse behaviors and prevalence between countries,” said Janetta L. Iwanicki, M.D., lead study investigator and Scientific Director of Research, Rocky Mountain Poison & Drug Safety, in a statement. 

“Despite high availability, tramadol has a low rate of misuse and abuse in the four countries. Importantly, consistent with previous literature, misuse of tramadol by injection, an important marker of risk behavior, is rare in these countries.”