Proposed User Instructions for OTC Narcan Has FDA Concerned

Ahead of an advisory committee meeting, FDA staff highlighted ongoing concerns about labeling for what could possibly be the first naloxone (Narcan) product approved for over-the-counter (OTC) use, labeling it "essential" in the emergency setting of an overdose.

At a joint meeting of the Nonprescription Drug Advisory Committee and Anesthetic and Analgesic Drug Products Advisory Committee on Wednesday, Emergent BioSolutions will present data and newly developed labeling for an OTC form of its nasal naloxone spray, which is already approved in prescription form. Advisors will be asked whether the risk-benefit profile supports the single-dose product's nonprescription use, or whether further data are needed.

The new instructions are aimed to quickly inform individuals without any healthcare training how to properly administer the emergency treatment, but FDA reviewers cited various issues, ranging from user errors like dialing 911 first (rather than administering a dose) to the possibility that each blister packaging may need to contain instructions as well, should users discard the box.

"We start with the assumption that the product may be in the hands of a naive user," FDA staff wrote in a briefing document released ahead of the meeting. "The design of the entire user interface plays an important role in how effective the product is at reversing opioid-induced respiratory depression and preventing death and other serious outcomes."

Since the proposed nonprescription version of the drug-device combo is "identical" to the prescription version in many ways, agency reviewers emphasized that the efficacy of naloxone "did not need to be reestablished," but more consideration would be needed to update the drug fact label (DFL) and packaging to prepare it for use by individuals without healthcare training.

"[I]t is unknown how access and availability of naloxone may shift with the switch from prescription to nonprescription status, but it is anticipated that a nonprescription status will remove one barrier to treatment for a life-threatening condition," FDA staff wrote.

The FDA has been heavily involved in the development of new labeling for OTC naloxone.

"In order to encourage naloxone applicants to enter the nonprescription market and to accelerate development of nonprescription naloxone, FDA took the unprecedented approach to study, develop, test, and validate a model naloxone [DFL]," according to agency staff.

Emergent Biosolutions utilized FDA's model, and supporting data for the application includes two studies on the potential efficacy of the DFL and package labeling in describing the proper use of the nasal spray.

In a label comprehension study, researchers evaluated the efficacy of labeling in describing the primary steps for using naloxone, including primary endpoints of identifying a potential overdose, administering a dose of the medication, and calling 911. Three additional primary endpoints included a combination of successfully completing the steps in order, repeating the steps if necessary, and staying with the patient until emergency personnel arrive. Among the eight primary endpoints, six of the prespecified thresholds were met or exceeded by the participants, according to the briefing document. Both of the primary endpoints not met involved step 3: "Call 911 immediately."

In a human factor validation study, 71 untrained adults and adolescents ages 15 and older were provided a "mock" OTC naloxone package, which contained two separately packaged drug-device products. Participants were asked to demonstrate how to administer the naloxone using the DFL instructions available on the packaging. The study revealed several errors in the participants' administration of naloxone, including starting with the wrong side of the packaging or spending additional time trying to find the next step of the instructions.

FDA is requesting that the advisory committees review proposed changes to the DFL and packaging, including whether to add a set of instructions within each product's blister package.

The prescription version of the single-dose nasal spray (which contains 4 mg of naloxone hydrochloride in 0.1 mL aqueous solution) was approved in 2015 for emergency situations involving suspected opioid overdose. While injection products are also available, these nasal products constitute 96.5% of the market.

Despite the widespread availability of prescription naloxone, healthcare professionals have continued to call for even greater accessibility to address the rise in overdose deaths. And FDA staff said the availability of OTC naloxone would "increase naloxone use because it would allow consumers concerned about potential stigma of opioid dependency to buy the product without hesitation or embarrassment of interacting with a pharmacist."

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