During late summer and fall of 2019, FDA panels have been voting on new and potent opioids. Some of these drugs have enhanced technology to deter abuse. One of the new drugs has no abuse deterrent at all, but instead provides a very strong sublingual dose meant especially for use in the battlefield when IV administration is not possible.
The FDA turned down one new drug applicant-Remoxy ER-prompting the manufacturer to shoot back with a claim that the decision was ideologically based.
And the administration was heavily criticized for approving another drug-sublingual sufentanil tablets-that had no abuse-deterrent qualities but is meant to be used only in credentialed health care settings for acute pain. The development of this sublingual sufentanil tablet was funded in part by the US Department of Defense.
Even in formulations that are developed to deter abuse, questions arise about how any one product can deter abuse in all the ways that addicts can find - intranasal, intravenous and oral routes, at the very least.
Manufacturer Claims Rejection on Ideological Grounds
In August, the FDA decided to uphold an earlier advisory panel vote of 14 to 3 against approving abuse-deterrent (AD) oxycodone extended-release (ER) capsules that were to be called Remoxy ER (Pain Therapeutics).
The Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees jointly voted 14 to 3 against recommending approval of the AD drug. Panel member John B. Hertig, PharmD, Center for Medication Safety Advancement at the College of Pharmacy, Purdue University, Indianapolis, said that he applauded the sponsor for being innovative, but that "when I'm balancing the risk-benefit and the availability of some similar options that are currently on the market compared with the possible public health impact, for me it was a no."1
The drug maker submitted documentation that Remoxy ER would deter injection, snorting and smoking, but made no claim about deterring oral abuse. Panel members were also concerned about the FDA's lab showing that material could still be extracted and used via the intravenous route, even though the abuse-deterrent agents cause the drug to turn to a gel if it is dissolved.
Pain Therapeutics president and chief executive officer Remi Barbier disputed the panel and administration's findings.
"We have an innovative drug with a social purpose, and a staggering amount of data that easily supports best-in-class abuse deterrence vs OxyContin," said Barbier. "I believe Remoxy received an ideological judgment call that is vague in nature but conclusive in damaging effects."1
Panel Advises Thumbs Up on New Immediate Release Oxycodone Formula
In November, two of the FDA advisory panels voted in a joint meeting to recommend approval of a request from Mallinckrodt Pharmaceuticals for new abuse-deterrent formulation (ADF) of immediate-release (IR) oxycodone hydrochloride tablets known as MNK-812, for the treatment of adult patients with severe pain.2
The vote by the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee was 10-7, with the two panels voting together. Several who voted yes noted the abuse-deterrent formula was at least a step in the right direction, and would replace a formulation that does not currently have abuse-deterrent properties.
However, several committee members and the consumer watchdog group Public Citizen raised concerns that the abuse-deterrent technologies weren't as robust as they would like, and did not deter abuse potential by oral routes.
The recommendation is to approve the IR drug for managing pain that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The new formulation is intended to replace the company's current branded and generic IR single-entity oxycodone tablets that have no abuse-deterrent properties.
The pharmaceutical company's application notes that the new formulation product has properties "intended to deter abuse by the nasal and intravenous [IV] routes utilizing both physical/chemical barriers to manipulation and incorporation of aversive agents into the formulation."
Several panel members explained their yes votes, including Lonnie Zeltzer, MD, director of the University of California-Los Angeles Pediatric Pain and Palliative Care Program, and a member of the Editorial Advisory Board of Topics in Pain Management.
"I voted yes because IR oxycodone is out there and it's abused. If this provides abuse deterrence to even a small percent of patients, then it's worth it," Zeltzer told Medscape Medical News.2
"There's a clear need for an abuse-deterrent formulation of immediate-release oxycodone," said acting chairperson of the joint meeting Brian T. Bateman, MD, associate professor at Harvard Medical School and chief of the Division of Obstetric Anesthesia at Brigham and Women's Hospital in Boston.2
"While the abuse-deterrent properties of this medication are perhaps not as robust as we might like, it is an important advance over the existing formulations," Bateman said. However, "there will be a real need for close surveillance of this product during the postmarketing period to detect any unintended consequences."
"Progression of Frustrations"
The abuse-deterrent qualities are described by the manufacturer as a "progression of frustrations" that start with a tablet that is not brittle but hard enough to be resistant to crushing into fine particles. Should a persistent individual manage to crush it and snort it, "aversive agents" in the formula will cause nasal irritation. And if someone were to try to crush it and dissolve it to inject with a syringe, it is designed to turn into a thick and sticky hydrogel that would be difficult for an addict to inject with a syringe.
Members of the panel, when voting specifically about what to recommend in labeling, seemed less convinced that the new formula should be labeled as abuse-deterrent by nasal route. More of the members voted to recommend labeling it as abuse-deterrent to IV syringe use.
Some members of the panel were concerned that MNK-812 could result in abuse after it is marketed, and need to be withdrawn, the way the FDA asked Endo Pharmaceuticals to remove its abuse-deterrent ER formulation of oxymorphone (Opana ER) from the market in June 2017.
There are currently 10 opioid analgesics labeled as having abuse-deterrent properties, all of which were approved after guidance was issued by the FDA in 2015. If approved by the FDA, MNK-812 will be required to be included in the opioid analgesic risk evaluation and mitigation strategy (REMS).
Sublingual Sufentanil Approved Amid Concerns, with Eye to Military Applications
In early November, the FDA approved a sufentanil sublingual tablet (Dsuvia, AcelRx) for adults for the management of acute pain that is severe enough to require an opioid analgesic in certified medically supervised health care settings, such as hospitals, surgical centers, and emergency departments.
It is expected to be marketed in the first quarter of 2019. The drug's development was co-funded by the US Department of Defense. It is a 30-mcg sufentanil tablet in a single-dose, prefilled applicator. The single-strength tablet and single-unit packaging are designed to mitigate the possibility of dosing errors, misuse, and diversion, according to AcelRx. (3)
"The sublingual administration makes Dsuvia an option for patients with nothing by mouth [NPO] status and patients with difficult IV access [obese, elderly, burn or needle-phobic patients]," the company wrote in a press statement. (3)
The FDA's approval of the drug was controversial. An FDA advisory committee recommended 10-3 in October that the agency approve the product. However, the panel's chairman, Raeford E. Brown Jr., MD, a professor of anesthesiology and pediatrics at the University of Kentucky, Lexington, wrote a letter to the FDA following the vote and stating his concerns. His letter called it "an easily divertible drug" that could lead to abuse, overdose, and death.
Sufentanil will not be available in retail pharmacies or for outpatient use. The manufacturer says it will distribute the drug only to health care settings certified in the Dsuvia REMS program.
Scott Gottlieb, MD, commissioner of the FDA, acknowledged the difficulties the agency faces in approving new drugs in the class during the current opioid epidemic. The clinical trials of the sublingual tablet demonstrate its efficacy in postoperative pain after abdominal surgery.
"I believe that the unique aspects of Dsuvia, including those that make this drug a high priority for the Pentagon, differentiate this new formulation of sufentanil from other sufentanil products in a way that is consistent with population-based considerations for how it fits into the overall drug armamentarium," Gottlieb said. "The FDA has made it a high priority to make sure our soldiers have access to treatments that meet the unique needs of the battlefield, including when intravenous administration is not possible for the treatment of acute pain related to battlefield wounds. The military application for this new medicine was carefully considered in this case."
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