Limited Evidence for Nalfmefene

"In 2021, due to the widespread availability of high-potency synthetic opioids like fentanyl, the US FDA approved two high-dose naloxone products, an 8 mg IN spray (Kloxxado) and a 5 mg IM injectable (Zimhi). The only studies reported in the FDA package inserts for both products are pharmacokinetic studies in healthy volunteers, which demonstrated substantially higher naloxone plasma levels than standard doses of naloxone (0.4 mg IM vs. 8 mg IN and 2 mg IM vs. 5 mg IM, respectively). In April 2024, based on a pharmacokinetic study of 30 healthy adult subjects, the FDA approved a 10 mg IN naloxone, Rezenopy. None of these approval trials was conducted among opioid overdose patients at risk for naloxone-precipitated withdrawal. In 2023, the FDA approved a 2.7 mg IN formulation of nalmefene (Opvee), a more potent and longer acting opioid antagonist than naloxone. The approval of nalmefene was also based on pharmacokinetic studies performed in healthy volunteers that showed higher plasma levels than standard naloxone doses and one pharmacodynamic study among opioid-experienced, but “non-depen­dent” participants which showed successful reversal of respiratory depression induced by laboratory administered remifentanil."