By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration has approved the first nalmefene autoinjector for the emergency treatment of known or suspected opioid overdose.1 Nalmefene is an opioid antagonist and an analog of naltrexone. It was granted a priority review and accelerated approval with a breakthrough therapy designation. It is distributed by Purdue Pharma L.P. as Zurnal.
An injectable nalmefene was approved in 1995 but was removed from the market by Baxter Healthcare Corporation in 2008 for “business reasons.”2 A nasal formulation was approved in May 2023 and marketed as Opvee by Indivior Inc.
Indications
Nalmefene is indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older as manifested by respiratory and/or central nervous system depression.3,4 It is intended for immediate administration as emergency therapy in a setting where opioids may be present.
Dosage
Nalmefene (autoinjector) should be injected (intramuscular or subcutaneous) into the anterolateral aspect of the thigh.3 It can be administered through clothing, if necessary. For the nasal spray, one spray can be administered intranasally. Medical assistance should be sought after the first dose. Additional doses may be required until emergency medical assistance becomes available.
If the patient responds and subsequently relapses back into respiratory depression before emergency assistance arrives, nalmefene may be readministered every two to five minutes. Nalmefene will be available as 1.5 mg/0.5 mL in a prefilled, single-dose autoinjector. The nasal spray is available as a unit-dose nasal spray device delivering a single spray containing 2.7 mg of nalmefene.
Potential Advantages
Nalmefene has a high affinity for the µ-opioid receptor and a significantly longer half-life than naloxone (eight to 11 hours vs. one to two hours).2 This may offer benefit against overdose with opioids with a longer half-life.2 It may prevent the recurrence of respiratory depression of long-acting opioid receptor agonists, such as fentanyl.2
Potential Disadvantages
Nalmefene may result in more prolonged and severe opioid withdrawal than naloxone.4 Patients who receive nalmefene may require a longer period of observation in the emergency setting and could increase resource use.5 It can produce acute withdrawal symptoms in individuals who are opioid-dependent.2,3 The most frequent adverse reactions are headache, nausea, dizziness, and nasal discomfort (for the intranasal spray).2,3
Comments
The approval of the autoinjector and nasal formulation is supported by safety and relative bioavailability compared to mainly intramuscular nalmefene.1-4 Nalmefene has an inherently slow absorption rate from the nasal passage, but it is enhanced with the addition of an absorption enhancer (dodecylmaltoside).2
Clinical Implications
There were more than 107,000 reported fatal overdoses in 2023, caused mainly by synthetic opioids (e.g., illicit fentanyl).1 There currently are two effective opioid antagonists — naloxone and nalmefene. The current Joint Position Statement of the American College of Medical Toxicology and the American Academy of Clinical Toxicology is that nalmefene should not replace naloxone as the primary opioid antidote at this time.5 The nalmefene autoinjector is expected to be available in 2025.
REFERENCES
- U.S. Food and Drug Administration. FDA approves first nalmefene hydrochloride autoinjector to reverse opioid overdose. Published Aug. 7, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-nalmefene-hydrochloride-auto-injector-reverse-opioid-overdose
- Britch SC, Walsh SL. Treatment of opioid overdose: Current approaches and recent advances. Psychopharmacology (Berl) 2022;239:2063-2081.
- Purdue Pharma L.P. Zurnal prescribing information. Published August 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218590s000lbl.pdf
- Indivior Inc. Opvee prescribing information. Revised May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217470Orig1s000.pdf
- Stolbach AI, Mazer-Amirshahi ME, Nelson LW, Cole JB. American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: Nalmefene should not replace naloxone as the primary opioid antidote at this time. Clin Toxicol 2023;61:952-955.
