On August 7 the Food and Drug Administration approved an opioid overdose antidote developed by Purdue Pharma that contains nalmefene, as opposed to the better-known naloxone. Zurnai is the second nalmefene product approved to treat opioid overdose, and the first to be formulated as an auto-injector. It’s expected to become available by prescription in 2025.
The fast-tracked approval reflects a long-planned strategic pivot to harm reduction by Purdue, which is attempting to rehabilitate its public image from the vitriol it earned for downplaying risks of OxyContin. The company is currently in bankruptcy court, negotiating the terms of its opioid settlement payouts.
In some states, standing orders—which effectively issue a prescription that covers everyone in the state so that they don’t have to obtain prescriptions individually—specify “naloxone.” But in others they’ve been encouraged to use broader language like “opioid overdose reversal agent,” which will make nalmefene products more accessible to the public.
Zurnai will join a market increasingly crowded with higher-dose, longer-acting opioid overdose reversal medications, which to date have no evidence demonstrating any benefit over Narcan or generic naloxone, and in some cases increase risk of death.
Opioid antagonists, which include nalmefene, naloxone and naltrexone, are effective at reversing overdose from any opioid—it doesn’t matter if it’s fentanyl or a fentanyl analogue or heroin or morphine. The reason they aren’t affected by potency is that they don’t actually act on the opioids themselves; they act on the receptors the opioids occupy.
However, rampant false claims by law enforcement, egged on by suggestive or open-ended marketing language from pharmaceutical companies, have created a narrative that naloxone is not powerful enough to keep up with increasingly powerful unregulated opioids. This supports investment in other opioid antagonists like nalmefene, which has a half-life—the time it takes for half the amount of a substance to exit someone’s system—of nearly 11 hours. Naloxone’s half-life is around one hour, which does not mean it’s less effective than nalmefene; it means it’s safer.
Generic intramuscular naloxone vials contain a solution of 0.4 ml because that’s the dose that will reach enough receptors to reverse an opioid overdose in the average adult. Going past that threshold to reach more receptors is redundant—once the person is breathing on their own, the overdose is over—but increases risk of precipitating withdrawal for people who use opioids regularly.
Precipitated withdrawal symptoms are the same as those of regular opioid withdrawal, but they develop almost instantaneously rather than over a period of hours and can’t be eased by using more opioids, as many people intuitively try to do. As a result, people desperate for relief may use doses far larger than than they normally would. This phenomenon can happen with naloxone, but it’s more likely to happen if the precipitated withdrawal lasts 11 times longer.
“We are working to distribute Zurnai at no profit,” a Purdue representative told Filter. “Purdue will not profit from its overdose rescue medicines or opioid use disorder treatments provided as part of its Public Health Initiatives. They are intended to help abate the opioid crisis and serve public health with no financial benefit.”
“[O]pioid intoxication and death” are not among the side effects listed on the FDA labeling for naloxone products, even higher-dose ones like the 8 mg Kloxxado and the 10 mg Rezenopy approved in April. But the warning does appear on the labeling for Zurnai, Vivitrol (long-acting naltrexone) and Opvee.
Opvee, a prescription nasal spray that looks similar to Narcan and other naloxone nasal sprays, contains 2.7 mg of nalmefene in each dose. It was the first nalmefene product to receive FDA approval. The agency announced the decision in May 2023, two months after it approved the first over-the-counter naloxone product.
In response to Filter‘s inquiry about Zurnai’s safety profile compared to naloxone’s, Purdue stated that its product “provides another treatment option” and then suggested that the risk of fatal overdose was created by the person who’d used opioids (emphasis Purdue’s):
“Zurnai, and other nalmefene products, come with the risk of opioid overdose from attempts to overcome the opioid blocking effects of nalmefene. Patients should be informed not to take large amounts of opioids to try to overcome the opioid-blocking effects of nalmefene. The risk of overdose death may occur if patients attempt to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of opioids.”
Zurnai is an auto-injector, which works along the same lines as an EpiPen. It contains 1.5 mg of nalmefene, which, since it’s injected into the muscle, hits the bloodstream more directly than when it’s sprayed into the nose.
The auto-injector is a more niche delivery mechanism for opioid antagonists, but it has precedent—the first naloxone product intended for community use, Evzio, was an auto-injector. It contained a 2 mg dose of naloxone and was initially popular when it got FDA approval in 2014, then quickly fell out of favor. This was partly because Narcan joined the market in 2015, and partly because around that time Evzio’s average out-of-pocket costs for uninsured patients abruptly spiked to over $1,000.
Manufacturer Kaleo, Inc. pulled Evzio, as well as a generic equivalent, from the market in 2020.
In 2021, Kaleo paid $12.7 million to settle allegations related to a kickback scheme in which the company would funnel Evzio prescriptions to specific pharmacies, which would then submit fake claims to insurers. According to the Justice Department, this included adding “false statements that patients had previously tried and failed less costly alternatives to Evzio.”
In 2022, the FDA nonetheless approved a Kaleo auto-injector containing 10 mg of naloxone. The company developed it for the Department of Defense, which claimed military personnel needed protection from potential terrorist attacks. The product is advertised as a defense for those responding to suspected deployment of “ultra-potent” opioids “such as fentanyl analogues as a chemical weapon.”
It appears to have also been discontinued.
Alongside cops and pharma companies, the FDA is also complicit in the public believing that nalmefene is somehow more advanced technology than naloxone, or that it’s not more harmful.
The agency’s explainer on the difference between the two fails to mention that one is labeled with fatal overdose as a potential risk, and the other is not—even after issuing a big public reprimand of naltrexone’s manufacturers for underplaying the same risk back in 2019. It also states that nalmefene is used “to treat acute opioid overdose” while naloxone simply “reverses opioid overdose.”
Top image (cropped) of Evzio auto-injector instructions via Indiana Department of Health. Inset image (cropped) of Evzio auto-injector via United Stated Food and Drug Administration.