The Food and Drug Administration’s (FDA) Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 8 “yes”, 14 “no” on whether the data provided to support the benefits of intravenous (IV) tramadol outweigh the risks for the management of acute pain severe enough to require an opioid analgesic in an inpatient setting.
The road for Avenue Therapeutics’ regulatory submission for tramadol IV has been a bumpy one. In December 2019, the Company had submitted a New Drug Application (NDA) that included data from two phase 3 clinical trials involving patients who were treated following bunionectomy or abdominoplasty, along with an open-label safety study and an epidemiology study. The NDA relied in part on the FDA’s findings of safety and efficacy for Ultram (tramadol HCl tablets).
Findings from the phase 3 trials showed that IV tramadol met all of the primary and most of the secondary endpoints. However, an analysis of the data by the FDA’s Division of Anesthesiology, Addiction Medicine, and Pain Medicine (DAAP) showed that tramadol IV had a delayed onset of analgesia, likely beyond 2 hours. This, the DAAP stated, raised the possibility for opioid stacking in patients whose pain was inadequately controlled with the first dose of tramadol IV. A Complete Response Letter (CRL) was sent by the Agency asking the Company to address the safety issue and identify a population for which the drug would be both safe and effective.
In February 2021, the Company resubmitted the NDA. The resubmission adequately addressed product quality deficiencies; however, it did not include any new clinical data. The Company also proposed a revised indication: management of moderate to moderately severe pain in adults in a medically supervised setting, alone or in combination with other analgesics. Hoping to address the potential concern of opioid stacking, the Company proposed adding language to the labeling recommending the use of nonopioid analgesics for patients who experience a delay in pain relief with tramadol IV.
Following the second review cycle, the FDA once again issued a CRL restating the initial safety concern. The DAAP noted that “intravenous opioid products are intended to be used in the management of pain that is not controlled by analgesics in other drug classes; therefore, therapy with an opioid for a painful condition that could be managed with a nonopioid is not consistent with the intended use of IV opioids.” The Division also stated that the studies included in the application were not designed to assess tramadol IV combined with other analgesics.
In response, the Company filed a formal dispute resolution request in July 2021 hoping to appeal the Complete Response decision. The dispute appeal was later denied. A second formal dispute resolution request was then submitted to the Office of New Drugs in September 2021. The reviewer concluded that additional input would be needed from an advisory committee before a decision on the appeal could be made.
The Office of New Drugs now has 30 calendar days following the advisory committee meeting to respond to Avenue Therapeutics formal dispute resolution request. The Company maintains that opioid stacking is not a safety concern and has not been shown to be one in countries outside of the US where IV tramadol is used.
- Avenue Therapeutics announces outcome of FDA advisory committee meeting on IV tramadol. News release. February 15, 2021. https://www.globenewswire.com/news-release/2022/02/16/2385819/0/en/Avenue-Therapeutics-Announces-Outcome-of-FDA-Advisory-Committee-Meeting-on-IV-Tramadol.html.
- FDA Briefing Information. February 15, 2021. https://www.fda.gov/media/156138/download.