STAMFORD, Conn.--(BUSINESS WIRE)--Purdue Pharma L.P. (“Purdue”) today announced The Journal of Clinical Pharmacology has published findings from a study in healthy adult volunteers that demonstrated in a clinical model of opioid induced respiratory depression (OIRD), intramuscular (IM) nalmefene (1 mg) reversed fentanyl-induced respiratory depression similar to or better than IM naloxone and intranasal (IN) naloxone.1 Imbrium Therapeutics L.P. (“Imbrium”), a subsidiary of Purdue, sponsored this study.
Nalmefene hydrochloride injection is an opioid antagonist indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids and in the management of known or suspected opioid overdose. Nalmefene hydrochloride injection is contraindicated in patients with a known hypersensitivity to the product.2 Nalmefene has the same pharmacological mechanism of action as naloxone. 3 Nalmefene has a long duration of action and provides another treatment option in reversing overdoses, including overdoses resulting from high doses of potent, long-acting synthetic opioids.3 While nalmefene has a long duration of action, health care providers should be aware that a recurrence of respiratory depression is possible. 2
Purdue Pharma distributes, for no profit, nalmefene injection in a 2mg/2mL (1mg/1mL) vial, as part of the Company’s commitment to providing opioid overdose treatments that can help save lives in communities across the country.
“As an R&D driven pharmaceutical company, we are committed to delivering solutions to help address the opioid crisis and conducting research to contribute to the growing body of scientific data about opioid antagonists,” said Craig Landau, MD, President and CEO, Purdue Pharma. “Studies like this are important to help advance our collective knowledge and build understanding of how nalmefene can help treat opioid overdoses.”
This replicate design, crossover study, using an OIRD model, investigated the onset and time course of action of nalmefene and naloxone in reversing the effects of fentanyl-induced respiratory depression defined as a reduction in respiratory minute volume (MV).
A three-step fentanyl infusion was administered to safely achieve and then maintain fentanyl concentrations sufficient to cause respiratory depression in OIRD. After fentanyl-induced respiratory depression was established, healthy adult participants aged 18-55, with a history of recent nonmedical opioid exposure, were randomized to receive IM nalmefene 1 mg, IM naloxone 2 mg, or IN naloxone 4 mg. The time course of reversal was monitored for 90 minutes following antagonist administration.
MV profiles showed that onset of reversal of fentanyl-induced respiratory depression occurred within the first five minutes following antagonist administration for all three treatments. However, the onset of reversal was earlier for IM nalmefene and IM naloxone, compared to IN naloxone. In addition, consistent with nalmefene’s half-life, the duration of reversal was longer with nalmefene, and the mean MV was maintained at a higher level through the end of the reversal session at 90 minutes following antagonist administration (see Figures 1 and S1 and Tables S3 and S4 in Reference 1).1
All participants experienced treatment-related adverse events (TEAEs), but none were severe, serious, or led to study drug discontinuation, and TEAEs were similar in all three treatment arms. The most commonly reported TEAEs by subjects in the study included hyperhidrosis (IM nalmefene, 25%; IM naloxone, 0%; IN naloxone, 12.5%); nausea (IM nalmefene, 25.0%; IM naloxone, 12.5%; IN naloxone, 0); and vomiting (IM nalmefene, 12.5%; IM naloxone, 12.5%; IN naloxone, 12.5%) (see Table S6 in Reference 1).1
Study limitations include the modest sample size, which was partially mitigated by administering each treatment twice, with the two administrations producing consistent results. Another limitation is that fentanyl concentrations were maintained approximately constant, which would not be expected to occur in a real-world setting. Further, pharmacodynamics were only analyzed up to 90 minutes after opioid antagonist administration, which meant that the duration of reversal could not be assessed beyond this point.
“Although the OIRD model is not a simulation of real-world opioid overdoses, it allows the magnitude and time course of reversal of fentanyl-induced respiratory depression to be directly compared between opioid antagonists,” said Sailaja Bhaskar, PhD, MBA, Vice President of Clinical R&D, Imbrium Therapeutics. “Additional studies and analysis of real-world data will further inform how nalmefene can be incorporated into opioid overdose treatment protocols.”
The increasing prevalence of fatal overdoses in the US involving synthetic, long-acting opioids, such as illicitly manufactured fentanyl and carfentanil, is a growing crisis.4-8 Provisional data for the 12 months ending February 2024 showed that approximately 90% of opioid overdose deaths were from synthetic opioids (primarily fentanyl).9 These data suggest the need for stronger, longer-acting opioid antagonist treatments.10 In 2017, the National Institutes of Health and National Institute on Drug Abuse jointly issued a call for the development of such treatments.11
IMPORTANT SAFETY INFORMATION
INDICATIONS AND USAGE
Nalmefene Hydrochloride Injection is indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids.
Nalmefene Hydrochloride Injection is indicated in the management of known or suspected opioid overdose.
CONTRAINDICATION
Nalmefene Hydrochloride injection is contraindicated in patients with a known hypersensitivity to the product.
WARNINGS AND PRECAUTIONS
Use of Nalmefene Hydrochloride injection in Emergencies
Nalmefene Hydrochloride injection, like all drugs in this class, is not the primary treatment for ventilatory failure. In most emergency settings, treatment with Nalmefene Hydrochloride injection should follow, not precede, the establishment of a patent airway, ventilatory assistance, administration of oxygen, and establishment of circulatory access.
Risk of Recurrent Respiratory Depression
Accidental overdose with long acting opioids [such as methadone and levo-alpha-acetylmethadol (LAAM)] may result in prolonged respiratory depression. Respiratory depression in both the postoperative and overdose setting may be complex and involve the effects of anesthetic agents, neuromuscular blockers, and other drugs. While Nalmefene Hydrochloride injection has a longer duration of action than naloxone in fully reversing doses, the physician should be aware that a recurrence of respiratory depression is possible, even after an apparently adequate initial response to Nalmefene Hydrochloride injection treatment.
Patients treated with Nalmefene Hydrochloride injection should be observed until, in the opinion of the physician, there is no reasonable risk of recurrent respiratory depression.
Cardiovascular Risks with Narcotic Antagonists
Pulmonary edema, cardiovascular instability, hypotension, hypertension, ventricular tachycardia, and ventricular fibrillation have been reported in connection with opioid reversal in both postoperative and emergency department settings. In many cases, these effects appear to be the result of abrupt reversal of opioid effects.
Although Nalmefene Hydrochloride injection has been used safely in patients with pre-existing cardiac disease, all drugs of this class should be used with caution in patients at high cardiovascular risk or who have received potentially cardiotoxic drugs.
Risk of Precipitated Withdrawal
Nalmefene Hydrochloride injection, like other opioid antagonists, is known to produce acute withdrawal symptoms and, therefore, should be used with extreme caution in patients with known physical dependence on opioids or following surgery involving high doses of opioids. Imprudent use or excessive doses of opioid antagonists in the postoperative setting has been associated with hypertension, tachycardia, and excessive mortality in patients at high risk for cardiovascular complications.
Incomplete Reversal of Buprenorphine
Preclinical studies have shown that nalmefene at doses up to 10 mg/kg (437 times the maximum recommended human dose) produced incomplete reversal of buprenorphine-induced analgesia in animal models. This appears to be a consequence of a high affinity and slow displacement of buprenorphine from the opioid receptors. Hence, Nalmefene Hydrochloride injection may not completely reverse buprenorphine-induced respiratory depression.
Use in Pediatric Patients
Safety and effectiveness of nalmefene hydrochloride injection in pediatric patients have not been established.
ADVERSE REACTIONS
The most common adverse reactions (>1%) reported in clinical trials with nalmefene injection were nausea (18%), vomiting (9%), tachycardia (5%), hypertension (5%), postoperative pain (4%), fever (3%), and dizziness (3%).
To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please read Full Prescribing Information available here.
For more information, visit www.nalmefenehcl.com.
About Purdue Pharma L.P.
Purdue Pharma and its subsidiaries develop, manufacture and market medications to meet the evolving needs of healthcare professionals, patients, and caregivers. Purdue and its subsidiaries focus on balancing innovative science with clinically effective, compassionate care. The Company’s goal is to serve patients who rely on its medicines, pursue its pipeline of branded and generic medications, and introduce medicines that will help save and improve lives. Purdue continues to work tirelessly with creditors to reach a new settlement that delivers billions of dollars of value for opioid crisis abatement.
For more information, visit www.purduepharma.com.
1Cipriano A, Apseloff G, Ram K, He E, Shet, M, Stephen H. Time course of reversal of fentanyl-induced respiratory depression in healthy subjects by intramuscular nalmefene and intramuscular and intranasal naloxone. J Clin Pharm. 2024. https://doi.org/10.1002/jcph.6132
2Nalmefene Hydrochloride Injection 2mg/2mL (1mg/1mL) [Full Prescribing Information]. Stamford, CT: Purdue Pharma L.P., 02/08/2022. https://www.accessdata.fda.gov/spl/data/d4bb0797-a4ed-4ed4-9904-604433eea4ff/d4bb0797-a4ed-4ed4-9904-604433eea4ff.xml. Accessed September 9, 2024.
3Edinoff AN, Nix CA, Reed TD, et al. Pharmacologic and clinical considerations of nalmefene, a long duration opioid antagonist, in opioid overdose. Psychiatry Int 2021;2(4):365-378.
4O'Donnell JK, Halpin J, Mattson CL, Goldberger BA, Gladden RM. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 - 10 States, July-December 2016. MMWR Morb Mortal Wkly Rep. 2017;66(43):1197-1202.
5O'Donnell J, Gladden RM, Mattson CL, Kariisa M. Notes from the Field: Overdose Deaths with Carfentanil and Other Fentanyl Analogs Detected - 10 States, July 2016-June 2017. MMWR Morb Mortal Wkly Rep. 2018;67(27):767-768.
6Baldwin GT, Seth P, Noonan RK. Continued Increases in Overdose Deaths Related to Synthetic Opioids: Implications for Clinical Practice. JAMA. 2021;325(12):1151-1152.
7Mattson CL, Tanz LJ, Quinn K, Kariisa M, Patel P, Davis NL. Trends and Geographic Patterns in Drug and Synthetic Opioid Overdose Deaths - United States, 2013-2019. MMWR Morb Mortal Wkly Rep. 2021;70(6):202-207.
8Ahmad FB, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. 2021. Available at: https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. Accessed March 28, 2022.
9Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. 2024. Available at: https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. Accessed September 4, 2024.
10Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2021:108019.
11Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. N Engl J Med. 2017;377(4):391-394.
MR-08592