FDA Proposes Prescription-to-OTC Naloxone

The agency is encouraging sponsors to submit applications for low-dose, nonprescription naloxone products.

The FDA issued a Federal Register notice, Safety and Effectiveness of Certain Naloxone Hydrochloride Drug Products for Nonprescription Use, that may help facilitate the development and approval of certain over-the-counter (OTC) naloxone drug products — including through the switch of certain naloxone drugs from prescription status to nonprescription status.

Naloxone is a medicine that can help reduce opioid overdose deaths and when administered timely — usually within minutes of the first signs of an opioid overdose — can counter the overdose effects, the agency said in a news release.

More than 80,000 people died of opioid-involved overdose deaths in the 12-month period ending in January 2022, up from 71,000 deaths in the preceding year, according to the FDA.

"Current evidence suggests that increasing access to naloxone has the potential to reduce opioid overdose deaths. Results from multiple observational studies show that naloxone distribution and overdose education targeted to populations likely to observe an overdose is an effective intervention strategy,” FDA said in the notice. “The public health benefits of FDA-approved prescription naloxone products in preventing overdose deaths clearly outweigh potential serious adverse reactions associated with naloxone administration,” the agency added.

The Federal Register notice includes a preliminary assessment that certain naloxone drug products — up to 4 mg nasal spray and up to 2 mg autoinjector for intramuscular or subcutaneous use — may be approvable as safe and effective for nonprescription use.

Ahead of the FDA announcement, Harm Reduction Therapeutics, a nonprofit pharmaceutical company, initiated a rolling submission for a new drug application (NDA) for RiVive (naloxone), as a nonprescription emergency treatment for opioid overdose. The first module has been submitted to the FDA, and the company expects the submission to be complete by the end of the year.

RiVive is an intranasal formulation of naloxone (3.0 mg) delivered as an atomized spray (0.1 ml) using a standard unit dose system for single administration. If approved, the company anticipates a launch of early 2024.

FDA’s notice does not cover all naloxone products, as more data are needed on the safety and efficacy for nonprescription use of higher dose naloxone products and naloxone supplied in other presentations (including vials, ampules or syringes without integrated needles) before a preliminary assessment with respect to those products can be reached, the agency said.

The FDA is requesting comments from the public on whether there is data to support safe and effective nonprescription use of higher dose naloxone products and on potential consequences of a switch from prescription to nonprescription status.

The risks associated with naloxone use also need to be considered, according to the FDA. “It is well-known that among patients with physical dependence to opioids, naloxone use may result in acute-onset, precipitated opioid withdrawal (precipitated withdrawal), referred to in the labeling for currently marketed naloxone products…” the agency said in the notice.

As noted in the labeling for currently approved naloxone products, naloxone-induced precipitated withdrawal may also be associated with other clinically serious adverse events such as pulmonary edema, cardiac arrythmias, and agitation, according to the agency.

“Despite these potential risks, the benefit of broader use of naloxone in reversing potentially fatal events is significant, even as surveillance for and mitigation of risks….resulting from administration of an opioid antagonist, should be considered mechanistically and clinically distinct from withdrawal resulting from cessation, or significant reduction in opioid use,” the FDA said.