Naloxone – an emergency opioid overdose reversal measure – is a good candidate for over-the-counter (OTC) designation. However, such an Rx to OTC switch raises some regulatory questions, including additional data needs and where a nonprescription naloxone product would fit into the market, especially as some formulations would stay prescription.
Background: Naloxone’s use and current regulatory status
- Naloxone is an emergency overdose reversal measure and is “the standard treatment for overdose.” As a nonselective and competitive opioid receptor agonist, naloxone can reverse central nervous system depression and respiratory distress caused by an opioid overdose. The product was first approved in the U.S. in 1971 under the trade name Narcan; routes of administration included injection and nasal administration via atomizer. However, rapid intervention is critical to prevent serious morbidity or death from opioid overdose, so there was a public health push to make naloxone easier to use, including Narcan “kits” to reduce the steps needed for administration. In 2014, FDA approved a pre-filled single-use auto-injector naloxone product (Evzio), and then in 2015 another Narcan formulation as a single-use nasal spray. In 2021, two new single-dose naloxone products entered the market with higher dose options: Kloxxado (nasal spray) and Zimhi (prefilled syringe).
- All approved naloxone products are currently prescription only – but there is significant flexibility in these requirements. The FDA maintains recommendations for health care professionals on the use of naloxone, requesting that they discuss or consider prescribing naloxone liberally, including to patients who are at increased risk of overdose (e.g., those prescribed both opioids and benzodiazapines or have experienced a previous overdose), those who are prescribed medication-assisted treatment (MAT, such as buprenorphine or methadone) or individuals known to have opioid use disorder (OUD). In addition, some of the available naloxone kits are approved by the FDA for “community use” – in effect, the sponsors submitted additional information that the products are intended to be easy to use by laypeople without the oversight of health care providers, requiring no assembly or additional supplies or materials. As the FDA outlined at a 2018 Advisory Committee meeting to discuss new “use in the community” indications and naloxone policy, community use aligns the regulatory considerations with the expected anticipated use of naloxone on the market; however, off-label use continues to be an issue, especially nasal administration of naloxone intended for parenteral administration, an issue the agency linked to priciness and difficulty accessing to newer formulations.
- State naloxone access laws have granted additional access to the product (see an explainer from SAMHSA’s Center for the Application of Prevention Technologies here). While the details and structure of these laws vary by state, they generally allow for different individuals and entities to carry and administer naloxone, typically through third-party prescriptions (prescribing naloxone to someone not at risk of overdose so that they can use the medication on someone else) or non-patient-specific prescriptions (authorizing naloxone distribution to individuals or entities who meet qualification criteria, or issuing standing orders to pharmacies within a certain jurisdiction). These types of laws, which sometimes carry training requirements, allow a variety of individuals and entities (e.g., first responders, case or outreach workers, harm reduction programs, public health and/or housing staff, law enforcement, members of the community) to carry and administer naloxone. Thus, in many cases people can now access naloxone without an individual prescription; for example, anyone who attends a local public health training session may be sent home with a harm reduction kit that includes naloxone, without ever seeing a prescriber, while public health and care workers may distribute kits to community members at their discretion.
- Since 2017, the opioid epidemic has been formally recognized as a public health emergency (PHE) under section 319 of the Public Health Services (PHS) Act. The PHE has been renewed regularly since 2017 – most recently in September 2022. The PHE declaration enabled a series of actions at the federal level, including new appointments of “specialized personnel,” new flexibilities in HIV/AIDS programs and policy measures to expand access to treatment for opioid-use disorder (OUD). For example, HHS’ Substance Abuse and Mental Health Services Administration (SAMHSA) issued new guidance under the PHE that allowed states with certain facilities known as Opioid Treatment Programs (OTPs) to allow methadone, a medication assisted treatment (MAT) for OUD, to be supplied to certain patients to “take home” (rather than having to administer the medication on site).
- The FDA has also released guidance on naloxone distribution under the PHE, effectively waiving certain requirements under the Drug Supply Chain Security Act (DSCSA) to entities that supply FDA-approved naloxone product to harm reduction programs and their suppliers. As the agency noted at the time, even with the flexibilities for prescribing naloxone that are in place both at the state and federal level, and under the PHE, “access to naloxone continues to be limited in some communities” – meaning that some individuals and caregivers are still unable to easily access overdose reversal tools. [See AgencyIQ’s analysis of that guidance here]
The FDA has now announced that some naloxone products would be appropriate for OTC use – but requests comment on how to address scientific and regulatory issues
- First: What exactly is this determination? The preliminary determination indicates that the FDA believes that naloxone would be a good candidate for a prescription to over-the-counter (OTC) switch. However, the preliminary assessment is not a final determination – “and it does not mandate an immediately effective switch to nonprescription/over-the-counter (OTC) availability for naloxone” – instead, it “is intended to facilitate development and approval of nonprescription naloxone products.” The determination lets sponsors know of “the possibility that the agency may make such a conclusive determination, through approval of a nonprescription drug product, that such products are safe and effective for use without a prescription.”
- The FDA is instead looking to shore up the viability of the path to such a switch. To make a final determination that naloxone can be appropriately classified as OTC, “the FDA needs additional data, such as product-specific data on the nonprescription user interface design, including packaging and labeling.” While the agency acknowledges that this information would typically be submitted in an application package, it seems that FDA is being more proactive – and rather than waiting to receive such data in a submission, it is actively seeking information now that could be used to support future OTC designation of certain naloxone products.
- For now, only certain naloxone products would be considered for OTC use, including up to 4 mgs in a nasal spray and up to 2 mg in an autoinjector for intramuscular or subcutaneous (IM or SC) use. Notably, the nasal spray is by far the most popular formulation of naloxone products – with over 95% of all naloxone dispensed as nasal spray in 2021, according to the FDA (although there are significant data gaps). Currently, higher dosage formulations are still too new to have sufficient evidence on their safety for OTC use, while other formulations (e.g., doses and syringes not as autoinjectors) are not being considered for nonprescription designation at this time. These formulations need additional preparation and supplies for administration, and thus are not specifically approved for community use.
- The process for a switch: Under 21 CFR 310.200, the FDA can exempt drugs from prescription-dispensing requirements when “such requirements are not necessary for the protection of the public health by reason of the drug’s toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and […] the drug is safe and effective for use in self-medication as directed in proposed labeling.” Notably, the proposal to switch a current prescription drug to a nonprescription status can be initiated by anyone – including the FDA itself (as is the case for naloxone).
The legal and regulatory process for an OTC switch presents some challenges
- As noted above, all currently approved naloxone products are prescription only, as outlined under the regulatory requirements at section 503(b) of the Federal Food, Drug and Cosmetics (FD&C) Act. Under this section of the law, all prescription products must include an “Rx only” symbol (at a minimum) on their labeling, or else they will be considered misbranded. However, the FDA does allow for simultaneous marketing of a prescription drug and a nonprescription drug with the same active ingredient – but only if there is a “clinically meaningful difference.” These can be design factors such as indication, strength, route of administration, dosage form, or patient population. Absent a “clinically meaningful difference,” however, simultaneous marketing of the same active ingredient drug product as both a prescription product and OTC “would result in the prescription drug product being misbranded.” In effect, if (and when) certain naloxone products become OTC, the prescription versions of that type of product would be misbranded.
- Currently, “we do not believe that any clinically meaningful differences could exist” between the existing prescription versions and those being considered for OTC switch (i.e., nasal spray up to 4 mg and/or autoinjector products up to 2 mg). This means that if the FDA were to approve an OTC naloxone product, the prescription versions of those products would be considered misbranded going forward. The Federal Register notice thus “strongly encourages application holders of prescription naloxone products described in this notice to contact FDA as early as possible to initiate a discussion about a possible switch.”
- The agency is asking for input about several specific issues here: First, whether there are clinically meaningful differences that could exist, and therefore allow for simultaneous marketing of OTC naloxone products and prescription versions. Second, the agency raises concerns that approving an OTC version, and therefore making the prescription products misbranded, could potentially disrupt access to these naloxone products. Per the notice in the Federal Register, the FDA questions whether there could be “potential consequences of a switch from prescription to nonprescription status for naloxone products,” up to and including drug shortages and the distribution and supply of naloxone.
- Nonprescription classification requires some additional evidentiary support, basically to demonstrate that the prescription requirement is “not necessary” per 21 CFR 310.200, including data that the drug product can be used safely without oversight from a provider. This can include additional studies “(e.g., label comprehension study, human factors study, and/or actual use study)” and labeling requirements under 21 CFR Part 201. The labeling for a nonprescription drug product is “commonly referred to as” the Drug Facts Label (DFL), which is intended to support individuals without oversight from a provider in safely and appropriately selecting and using nonprescription products.
- Notably, the FDA has, itself, developed model DFLs for naloxone. This project was intended to reduce regulatory barriers to developers considering an OTC naloxone product. The agency’s DFL models (one for an autoinjector, one for nasal administration) can be leveraged by sponsors seeking an OTC designation, without additional validation (unless they update the DFL).
- However, OTC designation also requires evidence and data. As mentioned above, the existing framework for naloxone distribution and access often does not require an individual prescription, and several naloxone products approved as a drug-device combination product (including Evzio, Narcan, Kloxxado and Zimhi) were approved as “community-use” products. These designs are intended “to facilitate use by laypersons” and without provider oversight, and with streamlined use considerations (e.g., no assembly, no additional supplies needed). Notably, these products are also approved by the FDA based on data demonstrating that “community use” administration methods are effective in reversing overdose. However, the OTC designation would take these evidentiary requirements a step further, requiring additional data to support a determination that the product would be safe and effective without the user(s) having any interaction with the health care system. While this is currently the lived reality of many who receive naloxone products (e.g., an individual who only contacts their local harm reduction group, rather than a provider treating them for substance use disorder), from a regulatory perspective the OTC designation would require additional data for FDA’s explicit sign-off.
- The agency is currently requesting comment on what that data would look like, and what it would need to include. Specifically, the agency is seeking input on what data would be needed to support safe and effective use of naloxone injection for IV, IM or SC use, and additional data that could potentially support safe and effective use of higher doses of nonprescription naloxone in either injection or nasal administration than originally considered in this notice.
- A final question: Is this necessary? As outlined above, state and local harm reduction and health care providers have found ways to bypass the prescription requirements, including through Narcan Access Laws (NAL). The FDA’s Federal Register notice requests input on the role that OTC naloxone could play, and whether taking action to approve nonprescription use would meaningfully benefit public health. Notably, the 2018 advisory committee highlighted several additional benefits to OTC products, including reduced stigma with the use/carrying of naloxone products and allowing kits specifically designed for lay use (currently community use products) to be used more broadly, as an alternative to off-label kits that require assembly and preparation. As the FDA and public health officials have also noted, access to naloxone is far from universal – and OTC availability could help reach new populations. However, the FDA’s concerns about disruptions to current supply chains are realistic, and would need to be factored into a rollout of nonprescription naloxone. Further, this change would require FDA to coordinate tightly with states as well as local public health and community stakeholders to ensure continued access within the context of often-tight budgets.
- What’s next? According to the notice, it appears that the FDA expects to move ahead with OTC naloxone approvals that it receives, and quickly – even urging sponsors of existing prescription product to get in touch as soon as possible to mitigate potential disruptions and make a plan. This is the next step in a long-standing priority for the FDA, which has sought to mitigate harms of historical opioid prescribing and the impact of opioid use disorder (OUD) over the last decade. Comments on the Federal Register notice will be accepted through January 15, 2023.