Originally published by our sister publication Pain Medicine News

Naloxone, an opioid receptor antagonist that reverses the effects of an opioid overdose, is now available over the counter, following approval by the FDA.

The approval comes about a month after two FDA advisory committees met and unanimously recommended that OTC naloxone be approved.

“If approved as a nonprescription product, naloxone nasal spray may be sold more broadly to the United States, in a greater variety of retail outlets, and may reduce the stigma for some obtaining an opioid reversal agent,” said Jody Green, MD, the deputy director of Safety, Division of Nonprescription Drugs, FDA Center for Drug Evaluation and Research, at a joint meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) in February.

Members of the committees ultimately agreed that the manufacturer, Emergent, had shown in its supplemental New Drug Application (sNDA) that the naloxone 4-mg nasal spray has an appropriate safety and benefit–risk profile for use as an OTC product.

Circuitous Route to Increasing Access
Although the opioid crisis was officially declared a public health emergency in October 2017, access to the naloxone antidote for opioid overdose has lagged well behind the availability of opioids. While approximately 1 million deaths between 1999 and 2021 have been attributed to drug overdose, principally from opioids, efforts to increase access to naloxone—even for harm reduction programs—were still meeting distribution and regulatory obstacles in 2022

States and their boards of pharmacy have acted with greater urgency than the FDA, with 14 states having established programs for providing naloxone without prescription by 2015, and all states and the District of Columbia doing so by 2022. However, the requirements and process for circumventing the FDA prescription classification differ among states, with most using a standing order to authorize naloxone and others requiring training before individuals can obtain the product without a prescription.

In September 2022, the FDA issued recommendations on expediting the availability of naloxone to harm reduction programs. In November 2022, the agency issued guidance to industry that would facilitate proposals, such as the sNDA from Emergent, for OTC designation. 

In her remarks, Green elaborated on several issues that the advisory committees would consider in their deliberations over whether to recommend or reject OTC status. She acknowledged that states have developed alternatives to the prescription requirement, but pointed out that these have left several potential barriers to access, such as the following: some pharmacists finding standing orders more complicated and choosing not to stock naloxone; the stigma of opioid dependence inhibiting purchases of naloxone through a pharmacist; and the persisting difficulty that harm reduction groups encounter in seeking to purchase bulk quantities.  

While OTC status could reduce those obstacles, Green emphasized that the committees would need to consider how consumer education and product packaging and labeling could facilitate correct use of the OTC naloxone in an emergency situation.

“[Naloxone’s nasal spray] efficacy as a prescription drug is well established, but is the proposed design of the user interface, including labeling, for the nonprescription drug optimized so that consumers will use it correctly without the help of a healthcare intermediary?” Green asked.

Considering Human Factors 
Sarah Farnsworth, PhD, the vice president of scientific affairs at PEGUS Research, in Salt Lake City, presented results of the Human Factors Validation Study, conducted for Emergent, to ascertain whether naloxone in the proposed packaging and labeling would be used correctly by participants from all representative user groups. The drug facts label for OTC products had been developed in consultation with the FDA (N Engl J Med 2020;382:2129-2136).

The open-label, multicenter study utilized in-person, one-on-one structured interviews. The interview room simulated the experience of discovering a family member in bed and unresponsive. A product carton containing two water-filled devices was on display, and participants were told to demonstrate how they would use the product to save their family member. Few directions and no prior training or exposure to the drug facts label were provided to participants, for the simulated overdose emergency to be as realistic as possible.  

The study primary end points included proper handling of the nasal spray (with thumb on the bottom of the plunger); proper insertion of the nozzle tip into either nostril of the overdose model; and firmly depressing the plunger to administer the first dose. The first two measures were achieved within the predefined performance threshold, while the third fell short, “but with an observed proportion of 94.4% of participants, with acceptable performance of this step,” Farnsworth said.

Recommending OTC Overdose Antidote
In their comments, committee members emphasized both the anticipated safety of the product as an OTC and the urgency to increase access to it. Speaking to the safety, for example, AADPAC member (temporary/voting) Jeffrey Brent, MD, PhD, a Distinguished Clinical Professor of Medicine at the University of Colorado (CU) School of Medicine and Colorado School of Public Health at CU Anschutz Medical Campus, in Aurora, said: “As a medical toxicologist, I can attest to the fact that naloxone is a very safe medication. I totally agree that giving it to somebody who is not opioid toxic will have no adverse effects on them.”

Diane Ginsburg, PhD, an NDAC member and a clinical professor of pharmacy practice at The University of Texas at Austin College of Pharmacy, possibly best summarized the sentiment of the joint meeting. “All of the evidence and data presented today is supportive of approving this drug to get to OTC, and hopefully we can leave today knowing that we are saving lives,” she said.

This sentiment also has been expressed by practitioners outside the meeting. Lewis Nelson, MD, the chair of emergency medicine and director of the Division of Medical Toxicology at Rutgers New Jersey Medical School and University Hospital in New Brunswick, discussed the recommended change in naloxone classification.

He contrasted the anticipated OTC with the current “behind-the-counter” status. “It changes the availability of the product in terms of the stigma associated with getting the medication, and just the simple availability of walking in and picking it up,” Nelson said.

Nelson also sought to allay concerns that OTC naloxone would be used inappropriately in a person affected by a nonopioid substance, or that it would be administered incorrectly. “Overwhelmingly, it will be safe to use in people who don’t have an opioid overdose,” he said.  

He anticipated that there would be a “learning curve” in properly holding the device and inserting the tip and administering the solution into the nostril, but expected that this would be facilitated by clear labeling, and taking time to review it before use. “It’s hard to learn in the moment of need,” Nelson said.

The benefits of expanding access through OTC designation far outweighed the associated risks, Nelson said. “It is clear that in order for naloxone to have its optimal public health benefit, it has to be immediately available for use. This means that it has to be accessible and affordable so that people carry it and stock it in places where it is reasonably likely to be needed.”

—Kenneth Bender

 Nelson reported no relevant financial disclosures.