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Opioid overdoses are full of unknowns. The variability and potency of opioids, particularly synthetics, make reversal situations even more challenging.2,3
Fentanyl and other synthetics (except methadone) increased opioid overdose deaths 7.5-fold from 2015–2021.
In 2021, this number increased to 70,601 overdose deaths—mostly from fentanyl.
*Includes deaths with underlying causes of unintentional drug poisoning (X40–X44), suicide drug poisoning (X60–X64), homicide drug poisoning (X85), or drug poisoning of undetermined intent (Y10–Y14), as coded in the International Classification of Diseases, 10th Revision.
Source: Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple Cause of Death 1999–2021. CDC WONDER Online Database, 01/23.
The National Institutes of Health (NIH) supports development of stronger, longer-acting formulations of opioid antagonists to counteract high-potency synthetic opioids.5
| Opioids | Drug | Plasma half-life (hours) |
|---|---|---|
Natural | Morphine6 | 3 to 4 |
Semisynthetic | Heroin7 | 0.5 |
Hydromorphone6 | 2 to 3 | |
Oxycodone8 | 3 to 5 | |
Synthetic | Fentanyl6, 9-11 | 2 to 8 |
Carfentanil12 | 5.7 | |
Tramadol13 | 6.3 | |
Methadone6 | >12 |
†This is not an exhaustive list of all opioids. Half-lives reported are approximations. Patient- and drug-specific variables may impact the actual half-life of a drug. Pharmacokinetic data may not necessarily correlate with clinical effects.
| Drug | Elimination mean plasma half-life (t1/2) | Route of administration Route of admin-istration |
|---|---|---|
Nalmefene HCl1injection | 10.8 hours§ | IV, IM, or SC |
Naloxone HCl (generic)14injection | 0.5–1.35 hours | |
ZIMHI® | IM, 1.5 hours | IM or SC |
OPVEE® (nalmefene)16nasal spray | 11.4 hours | IN |
NARCAN® (naloxone HCl)17nasal spray | Approximately 2.08 hours | |
Kloxxado® (naloxone HCl)18nasal spray | 1.8–2.7 hours | |
RiVive™ | 1.36 hours |
IM=intramuscular; IN=intranasal; IV=intravenous; SC=subcutaneous.
‡Not an exhaustive list of all half-lives reported across all studies conducted. Based on values reported in each respective full Prescribing Information and New Drug Application.
§Nalmefene elimination half-life is based on pharmacokinetic data. The mean terminal elimination half-life is 10.8 hours and 9.4 hours in
Effectively reversed respiratory depression within
10.8-hour mean terminal elimination half-life1¶
Safety and tolerability similar to naloxone1
Flexibility to be given as IV, IM, or SC injection1
IM=intramuscular; IV=intravenous; SC=subcutaneous.
Studied in 284 patients presumed to have taken an opioid overdose. Effectively reversed respiratory depression at doses of 0.5 mg to 1 mg. Dose range in clinical trials was 0.5 mg to 2 mg.1,20
Nalmefene elimination half-life is based on pharmacokinetic data. The mean terminal elimination half-life is 10.8 hours and 9.4 hours in younger (19 to 32 years) and elderly (62 to 80 years) healthy male subjects, respectively, following a Nalmefene HCl 1 mg IV dose.1
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.
IMPORTANT SAFETY INFORMATION
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 .
Please see .
References: 1. Nalmefene HCl Injection Full Prescribing Information. Purdue Pharma L.P.; 2022. 2. Edinoff AN, Martinez Garza D, Vining SP, et al. New synthetic opioids: clinical considerations and dangers. Pain Ther. 2023;12(2):399-421. doi:10.1007/s40122-023-00481-6. 3. Larnder A, Saatchi A, Borden SA, et al. Variability in the unregulated opioid market in the context of extreme rates of overdose. Drug Alcohol Depend. 2022;235:109427. doi:10.1016/j.drugalcdep.2022.109427. 4. National Institute on Drug Abuse. Drug overdose death rates. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates. February 9, 2023. Accessed June 26, 2023. 5. National Institute on Drug Abuse. Naloxone drug facts. https://nida.nih.gov/publications/drugfacts/naloxone. June 2021. Accessed June 26, 2023. 6. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi:10.1097/CCM.0b013e3182783b72. 7. Lautieri A. How long does heroin stay in your system? American Addiction Centers. https://americanaddictioncenters.org/heroin-treatment/how-long-in-system. Updated September 9, 2022. Accessed June 26, 2023. 8. How long do opiates stay in your system? American Addiction Centers. https://americanaddictioncenters.org/prescription-drugs/how-long-in-system. Updated September 9, 2022. Accessed June 26, 2023. 9. Fentanyl Citrate Injection Full Prescribing Information. Akorn, Inc.; 2012. 10. Holley FO, Van Steennis C. Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodynamics of constant-rate i.v. and transdermal delivery. Br J Anaesth. 1988;60(6):608-613. doi:10.1093/bja/60.6.608. 11. Ahonen J, Olkkola KT, Hynynen M, et al. Comparison of alfentanil, fentanyl and sufentanil for total intravenous anaesthesia with propofol in patients undergoing coronary artery bypass surgery. Br J Anaesth. 2000;85(4):533-540. doi:10.1093/bja/85.4.533. 12. Leen JLS, Juurlink DN. Carfentanil: a narrative review of its pharmacology and public health concerns. Can J Anaesth. 2019;66(4):414-421. doi:10.1007/s12630-019-01294-y. 13. Ultram® Full Prescribing Information. Janssen Pharmaceutical Companies; 2019. 14. Naloxone Hydrochloride Injection Full Prescribing Information. Hospira, Inc.; 2023.
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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.
IMPORTANT SAFETY INFORMATION
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 .
Please see .
References: 1. Nalmefene HCl Injection Full Prescribing Information. Purdue Pharma L.P.; 2022. 2. Edinoff AN, Martinez Garza D, Vining SP, et al. New synthetic opioids: clinical considerations and dangers. Pain Ther. 2023;12(2):399-421. doi:10.1007/s40122-023-00481-6. 3. Larnder A, Saatchi A, Borden SA, et al. Variability in the unregulated opioid market in the context of extreme rates of overdose. Drug Alcohol Depend. 2022;235:109427. doi:10.1016/j.drugalcdep.2022.109427. 4. National Institute on Drug Abuse. Drug overdose death rates. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates. February 9, 2023. Accessed June 26, 2023. 5. National Institute on Drug Abuse. Naloxone drug facts. https://nida.nih.gov/publications/drugfacts/naloxone. June 2021. Accessed June 26, 2023. 6. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi:10.1097/CCM.0b013e3182783b72. 7. Lautieri A. How long does heroin stay in your system? American Addiction Centers. https://americanaddictioncenters.org/heroin-treatment/how-long-in-system. Updated September 9, 2022. Accessed June 26, 2023. 8. How long do opiates stay in your system? American Addiction Centers. https://americanaddictioncenters.org/prescription-drugs/how-long-in-system. Updated September 9, 2022. Accessed June 26, 2023. 9. Fentanyl Citrate Injection Full Prescribing Information. Akorn, Inc.; 2012. 10. Holley FO, Van Steennis C. Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodynamics of constant-rate i.v. and transdermal delivery. Br J Anaesth. 1988;60(6):608-613. doi:10.1093/bja/60.6.608. 11. Ahonen J, Olkkola KT, Hynynen M, et al. Comparison of alfentanil, fentanyl and sufentanil for total intravenous anaesthesia with propofol in patients undergoing coronary artery bypass surgery. Br J Anaesth. 2000;85(4):533-540. doi:10.1093/bja/85.4.533. 12. Leen JLS, Juurlink DN. Carfentanil: a narrative review of its pharmacology and public health concerns. Can J Anaesth. 2019;66(4):414-421. doi:10.1007/s12630-019-01294-y. 13. Ultram® Full Prescribing Information. Janssen Pharmaceutical Companies; 2019. 14. Naloxone Hydrochloride Injection Full Prescribing Information. Hospira, Inc.; 2023.
