The FDA Tackles the Approval of New Opioid Medication

Michael Nguyen, PharmD, Director of Clinical Services
Nancy Wood, PharmD candidate and Philadelphia College of Osteopathic Medicine

The U.S Food and Drug Administration (FDA) recently reviewed two new opioid medications for approval – Dsuvia® and Olinvo®. The crisis of opioid addiction is a great concern in our country. The FDA is taking steps to actively confront this crisis, while also keeping the needs of the patients and physicians a priority. The FDA approved Dsuvia for use but denied approval for Olinvo. Dsuvia has unique features that made it a priority of not just the FDA but also the Department of Defense. Olinvo was not able to prove safety and efficacy above what is already on the market.

What is Dsuvia and why is it useful?

Dsuvia is a Schedule II opioid analgesic for the management of moderate to severe pain in adults. Dsuvia is a 30-mcg tablet, packaged in a special single-use applicator, that dissolves under the tongue and begins working to relieve pain in under an hour. It is a different formulation of an already available drug called sufentanil, which prior to Dsuvia was only available for IV use as an anesthetic for surgeries and other invasive medical procedures.

Dsuvia is designed to mitigate the possibility of dosing errors, misuse, and diversion. A main problem with current opioids is that they are mixed up because of similar packaging. Of the opioid-related adverse drug events – including death – that occurred in hospitals and were reported to the Joint Commission’s Sentinel Event database (2004-2011), 46% were wrong dose medication errors. The approval indicates the opioid is only to be used in certified medically supervised health care settings, such as hospitals, surgical centers, and emergency departments.

Dsuvia serves a purpose that no other opioid does. It provides an alternative for rapid pain relief in austere settings like the battlefield, and therefore, it fulfills the FDA’s new criteria for approval.  Restrictions are in place to mitigate the potential for abuse. The drug must be dispensed in pre-filled syringes, use is limited to 72 hours, and it is to be used only in hospital and health care settings. Dsuvia will not be available in retail pharmacies for outpatient use. It will only be distributed to health care settings certified in the Dsuvia risk evaluation and mitigation strategy (REMS) program following attestation by an authorized representative that the health care setting will comply with appropriate dispensing and use restrictions. Dsuvia is to be reserved for use in patients for whom alternative treatment options have not been tolerated or have not been shown to be effective. Dr. Pamela Palmer, co-founder and chief medical officer of AcelRx said the new drug would help patients whose pain cannot be treated efficiently with an IV or an injection, such as soldiers on the battlefield or patients whose veins are difficult to find. The sublingual administration makes it an option for patients with nothing by mouth (NPO) status and patients with difficult IV access (obese, elderly, burn, or needle-phobic patients).

Dsuvia is expected to launch in the first quarter of 2019.

What is Olinvo and why was it not approved?

Olinvo (oliceridine) is a new intravenous opioid known as a G-protein biased mu-opioid receptor (MOR) ligand that is meant for the management of moderate to severe pain for patients in hospitals or other controlled clinical settings. Olinvo was denied FDA approval because of “inadequate safety data” and “potential for abuse.” Olinvo (an opioid) is marketed as “being as effective as morphine at relieving pain and poses less risk of depressing breathing.”

Olinvo has a unique mechanism of action that allows for more selective pathway activation while avoiding a pathway associated with opioid-related adverse events. Preclinical studies show a reduction in the activation the neurological pathway that trigger reactions leading to adverse events or side effects, and hopes were that it could reduce sedation, respiratory depression, and gastrointestinal events. Although Olinvo demonstrated efficacy over placebo in clinical trials, the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) expressed concerns that the proposed dosing may not be sufficient to treat moderate to severe pain and that higher doses may lead to adverse events such as cardiac arrhythmia (QT prolongation) and respiratory depression. It failed to show superiority over existing opioid options. While potential was seen with Olinvo, the comparisons with current opioids were not done at the same doses. The phase III clinical trials showed less respiratory suppression and fewer side effects than morphine at a lower dose, but the improvements did not reach statistical significance for higher doses. The company proposed an initial dosing of 1 to 2 mg every 1 to 3 hours as needed, with patient-controlled analgesia doses of 0.1 to 0.35 mg, for a maximum of 40 mg per day. The concern was that the trial population was not large enough to have accurate data on how the dosing would affect children and the elderly. Trevena, Inc., the manufacturer of Olinvo, plans to conduct more trials before re-submitting a new drug application for Olinvo. This indicates that the drug will not be approved anytime soon.

Why does the FDA keep approving new opioids?

With the opioid epidemic in full swing, the FDA is encountering a lot of criticism when approving new opioids.  The fact that the FDA enlists the guidance of an advisory committee before making approval rulings does not seem to lessen the media scrutiny.[1]The FDA’s ruling on Dsuvia and Olinvo was consistent with the recommendations from the advisory committees assigned to review them.  For these two new medications, the advisory committees voted 10-3 in favor of approving Dsuvia and 8-7 against approving Olinvo.

It is a tough job, but the FDA’s fundamental goal is to ensure that pharmaceuticals marketed in the U.S. are safe and effective for the public. In regards to opioids, it appears that there is an additional criterion: does the new opioid provide enhanced value, which these days means that the medication may be safer or provide an alternative treatment option that was not previously available? With new pill forms of opioids, the FDA is encouraging the incorporation of abuse deterrent technology to make opioids safer.

Dsuvia provides an alternative treatment option to intravenous opioid administration. The high potency of sufentanil and the sublingual administration was intended to mimic the fast relief that can be achieved by intravenous opioid administration. If Dsuvia is as effective as intravenous opioids for acute pain, it can prove to be safer because adverse reactions such as infection related to IV medication administration can be avoided. Dsuvia also provides an alternative treatment option when intravenous administration is not available or is less efficient, such as the battlefield.

Olinvo could have been approved if its NDA was in order. The advisory committee’s vote was narrow (8-7).  Perhaps the seven members who voted to approve Olinvo were optimistic about the drug’s ability to treat pain like any other opioid while avoiding activation of the neurological pathway that leads to opioid-associated side effects. If the makers of Olinvo can prove this in their resubmission of the NDA, it is highly likely that the drug would be approved because its developers intended it to be a safer option than the existing intravenously administered opioids.

Sometimes it is easy to vilify the FDA since the agency does have the authority to reject any new drug application, but considering their overall goal is to ensure the safe and effective use of medication, the FDA must thoroughly review all drug applications for any signs of innovation that would further this goal, even opioids.

https://www.prnewswire.com/news-releases/acelrx-announces-fda-approval-of-dsuvia-300743221.html

https://www.pharmacytimes.com/resource-centers/pain/sufentanil-sublingual-tablet-dsuvia-gets-fda-approval’

https://www.drugs.com/history/dsuvia.html

https://www.empr.com/news/dsuvia-sufentanil-sublingual-acute-pain-medically-supervised-healthcare-settings-approval/article/812353/

https://www.trevena.com/Oliceridine.php


[1] https://www.statnews.com/pharmalot/2018/11/02/fda-dsuvia-fentanyl-approval/

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