Version May 2024
Note: Use of opioid antagonists in most emergency settings should be done in conjunction with establishment of a patent airway, ventilatory assistance, administration of oxygen, and circulatory access.
Opioid overdose:
Note: For the initial treatment of an opioid-associated life-threatening emergency, the American Heart Association recommends, after initiation of CPR, the use of intranasal or IM naloxone with a repeat dose as needed; nalmefene may also be considered for treatment of an opioid-associated life-threatening emergency. If there is an initial patient response (ie, purposeful movement, regular breathing, moan or other response) but the patient then stops responding, begin CPR and administer a repeat dose of the opioid antagonist (eg, naloxone, nalmefene). If no initial response, continue CPR and use automated external defibrillator as appropriate (AHA [Panchal 2020]).
IV (preferred [AHA {Panchal 2020}]), IM, SUBQ:
Non–opioid-dependent patients: IV (preferred [AHA {Panchal 2020}]), IM, SUBQ: Initial: 0.5 mg; if needed, a second dose of 1 mg may be administered 2 to 5 minutes later (Kaplan 1999). If there is no clinical response following a total dose of 1.5 mg, it is unlikely that continued administration of nalmefene will be beneficial. Do not administer additional nalmefene once adequate initial reversal has been established.
Recurrent respiratory depression: Patients who achieved adequate reversal with the initial dosing regimen but experience recurrent respiratory depression may receive additional nalmefene using the same dosing strategy as described for initial therapy.
Opioid-dependent patients: IV (preferred [AHA {Panchal 2020}]), IM, SUBQ: Initial: 0.1 mg; if there is no evidence of withdrawal, administer 0.5 mg. If needed, a repeat dose of 1 mg may be administered 2 to 5 minutes later (Kaplan 1999). If there is no clinical response following a total dose of 1.6 mg, it is unlikely that continued administration of nalmefene will be beneficial. Do not administer additional nalmefene once adequate initial reversal has been established.
Recurrent respiratory depression: Patients who achieved adequate reversal with the initial dosing regimen but experience recurrent respiratory depression may receive additional nalmefene using the same dosing strategy as described for initial therapy.
Intranasal: 2.7 mg (contents of 1 nasal spray) as a single dose in 1 nostril; may repeat every 2 to 5 minutes as needed in alternating nostrils for continued or recurrent respiratory depression until medical assistance becomes available. A new nasal spray is required for each dose.
No dosage adjustment necessary.
No dosage adjustment necessary.
Refer to adult dosing.
Nalmefene may precipitate opioid withdrawal syndrome in patients with opioid dependence or opioid use disorder. Symptoms may include abdominal pain, agitation, diaphoresis, diarrhea, fever, hypertension, hypotension, irritability, nausea, tachycardia, and vomiting. Withdrawal symptoms may require hospitalization, but are rarely life-threatening (Ref).
Mechanism: Related to the pharmacologic action; nalmefene acts as a competitive antagonist at opioid receptors, precipitating withdrawal (Ref).
Onset: Rapid; within 15 minutes to 3 hours (Ref).
Risk factors:
• Higher doses or shorter intervals between doses
• Preexisting cardiac disease
• Concurrent medications with adverse cardiovascular effects
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for injectable (IV) and nasal spray (intranasal) formulations, unless otherwise noted.
>10%:
Endocrine & metabolic: Hot flash (intranasal: 20%)
Gastrointestinal: Nausea (intranasal: 3% to 36%; IV: 18%) (table 1), vomiting (2% to 12%) (table 2)
|
Drug (Nalmefene) |
Comparator (Naloxone) |
Placebo |
Dosage Form |
Number of Patients (Nalmefene) |
Number of Patients (Naloxone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
36% |
N/A |
N/A |
Intranasal |
61 |
N/A |
N/A |
|
18% |
18% |
6% |
IV |
1,127 |
369 |
77 |
|
3% |
N/A |
N/A |
Intranasal |
89 |
N/A |
N/A |
|
Drug (Nalmefene) |
Comparator (Naloxone) |
Placebo |
Dosage Form |
Number of Patients (Nalmefene) |
Number of Patients (Naloxone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
12% |
N/A |
N/A |
Intranasal |
61 |
N/A |
N/A |
|
9% |
7% |
4% |
IV |
1,127 |
369 |
77 |
|
2% |
N/A |
N/A |
Intranasal |
89 |
N/A |
N/A |
Nervous system: Anxiety (intranasal: 12%), dizziness (intranasal: 6% to 15%; IV: 3%), headache (intranasal: 7% to 56%)
Respiratory: Nasal discomfort (intranasal: 8% to 43%)
1% to 10%:
Cardiovascular: Hypertension (IV: 5%) (table 3), hypotension (IV: 1%), tachycardia (IV: 5%) (table 4), vasodilation (IV: 1%)
|
Drug (Nalmefene) |
Comparator (Naloxone) |
Placebo |
Dosage Form |
Number of Patients (Nalmefene) |
Number of Patients (Naloxone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
5% |
7% |
0% |
IV |
1,127 |
369 |
77 |
|
Drug (Nalmefene) |
Comparator (Naloxone) |
Placebo |
Dosage Form |
Number of Patients (Nalmefene) |
Number of Patients (Naloxone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
5% |
8% |
0% |
IV |
1,127 |
369 |
77 |
Dermatologic: Diaphoresis (intranasal: 7%), erythema of skin (intranasal: 3%)
Gastrointestinal: Abdominal pain (intranasal: 1% to 2%), decreased appetite (intranasal: 1% to 3%), dysgeusia (intranasal: 1% to 3%), xerostomia (≤2%)
Nervous system: Agitation (intranasal: 3%; IV: <1%), chills (1% to 3%), claustrophobia (intranasal: 3%), fatigue (intranasal: 3% to 5%), insomnia (intranasal: 1%), paresthesia (intranasal: 3%)
Respiratory: Dyspnea (intranasal: 3%), nasal cavity pain (intranasal: 2% to 3%), nasal congestion (intranasal: 3% to 5%), oropharyngeal pain (intranasal: 3%), rhinitis (intranasal: 1%), throat irritation (intranasal: 3% to 5%)
Miscellaneous: Fever (IV: 3%) (table 5)
|
Drug (Nalmefene) |
Comparator (Naloxone) |
Placebo |
Dosage Form |
Number of Patients (Nalmefene) |
Number of Patients (Naloxone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
3% |
4% |
0% |
IV |
1,127 |
369 |
77 |
<1%:
Cardiovascular: Bradycardia (IV), cardiac arrhythmia (IV)
Dermatologic: Pruritus (IV)
Gastrointestinal: Diarrhea (IV)
Genitourinary: Urinary retention (IV)
Hepatic: Increased serum aspartate aminotransferase (IV)
Nervous system: Confusion (IV), depression (IV), drowsiness (IV), myoclonus (IV), nervousness (IV), opioid withdrawal syndrome (IV) (Yéléhé-Okouma 2017), tremor (IV)
Respiratory: Pharyngitis (IV)
Hypersensitivity to nalmefene or any component of the formulation.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease or in patients receiving medications with potential adverse cardiovascular effects (eg, hypotension, pulmonary edema, arrhythmias); pulmonary edema and cardiovascular instability, including ventricular fibrillation, have been reported in association with abrupt reversal when using opioid antagonists.
Other warnings/precautions:
• Opioid overdose: When compared to naloxone, nalmefene has a longer duration of action at fully reversing doses; however, prolonged or recurrent respiratory depression is possible if the opioid involved is long-acting (eg, methadone, levo-alpha-acetylmethadol); recurrence of respiratory depression may occur even with an adequate initial response to nalmefene; continuously observe patients until there is no further risk of recurrent respiratory depression. Illicit use of high or repeated doses of exogenous opioids in an attempt to curb nalmefene-induced withdrawal symptoms is associated with a risk of acute opioid intoxication and/or death.
• Opioid use disorder: To prevent overdose deaths, there are initiatives to dispense an opioid antagonist (ie, naloxone, nalmefene) for self- or buddy-administration to patients at risk of opioid overdose (eg, recipients of high-dose opioids, suspected or confirmed history of illicit opioid use) and individuals likely to be present in an overdose situation (eg, family members of illicit drug users) (Albert 2011; Bennett 2011). Clinical practice guidelines recommend patients being treated for opioid use disorder should be given prescriptions for an opioid antagonist (ie, naloxone, nalmefene). Patients and family members/significant others should be trained in the use of opioid antagonists (ie, naloxone, nalmefene) in overdose (ASAM 2020). Intranasal products (eg, Opvee) are indicated for emergency treatment. There is a low incidence of death following naloxone reversal of opioid toxicity in patients who refuse transport to a health care facility (Wampler 2011). Nevertheless, patients who received an opioid antagonist (ie, naloxone, nalmefene) in the out-of-hospital setting should seek immediate emergency medical assistance after the first dose due to the likelihood that respiratory and/or CNS depression will return.
• Partial opioid agonist-induced respiratory depression: Reversal of respiratory depression secondary to a partial opioid agonist (eg, buprenorphine) may be incomplete; larger or repeat doses of nalmefene may be required.
• Postoperative reversal: Appropriate use: Excessive dosages should only be used with extreme caution after use of opioids in surgery. Abrupt postoperative reversal may result in nausea, vomiting, tachycardia, hypertension, seizures, and other cardiovascular events (including pulmonary edema and arrhythmias).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection [preservative free]:
Generic: 1 mg/mL (2 mL)
Solution, Nasal, as hydrochloride:
Opvee: 2.7 mg/0.1 mL (1 ea, 2 ea) [latex free; contains benzalkonium chloride, disodium edta]
Yes
Solution (Nalmefene HCl Injection)
1 mg/mL (per mL): $18.00
Solution (Opvee Nasal)
2.7MG/0.1ML (per each): $58.80
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IV: Administer via rapid IV push (preferred); IM or SUBQ administration may be utilized if IV access is lost or not readily available. In patients with kidney failure, consider slow administration over 60 seconds to minimize hypertension and dizziness.
Intranasal: For use in nostril only. Administer initial dose as soon as possible. Do not prime or test the device prior to administration. Administer in alternating nostrils with each dose. Place the patient in the supine position and provide support to the back of the neck to allow the head to tilt back. If patient responds to the dose by waking up to the voice or touch or starts breathing normally, turn them on their side. Each device contains a single intranasal spray, do not reuse; if repeat administration is necessary, a new device must be used.
Opioid overdose: For the complete or partial reversal of opioid drug effects, including respiratory and/or CNS depression, induced by either natural or synthetic opioids; also indicated in the management of known or suspected opioid overdose.
Intranasal (Opvee): For the emergency treatment of known or suspected opioid overdose as manifested by respiratory and/or CNS depression in adults and pediatric patients ≥12 years of age. Intended for immediate administration as emergency therapy in settings where opioids may be present. Not a substitute for emergency medical care.
Nalmefene may be confused with nalbuphine.
Substrate of CYP3A4 (minor), UGT1A3, UGT1A8, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Opioid Agonists: Nalmefene may diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification
Outcome data following maternal use of nalmefene during pregnancy are limited and not specific to use following opioid exposure (Chick 2021; López-Pelayo 2020).
Based on data from other opioid antagonists, use may precipitate opioid withdrawal in the fetus in addition to the mother (ACOG 2017). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant patients if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).
It is not known if nalmefene is present in breast milk.
Respiratory rate, heart rate, BP, temperature, level of consciousness, arterial blood gas, or pulse oximetry.
As a 6-methylene analog of naltrexone, nalmefene acts as a competitive opioid receptor antagonist, thereby reversing the respiratory depression induced by opioids. When compared to naloxone, nalmefene has a longer duration of action and a higher affinity for opioid receptors (France 2021; Krieter 2019).
Onset: IV: 2 to 5 minutes; IM, SUBQ: 5 to 15 minutes; Intranasal: 2.5 to 5 minutes.
Duration:
IV:
Partially reversing doses (ie, 1 mcg/kg): 30 to 60 minutes.
Fully reversing doses: >4 hours and relatively longer when compared to naloxone (Glass 1994).
Distribution: Vdss: 8.6 ± 1.7 L/kg.
Protein binding: 45%.
Metabolism: Hepatic primarily via glucuronide conjugation to an inactive metabolite; also metabolized to trace amounts of an N-dealkylated metabolite (inactive). May undergo enterohepatic recycling (Dixon 1986).
Bioavailability: IM, SUBQ: ~100%; Intranasal: ~80%.
Half-life elimination: ~11 hours.
Time to peak: IM: 2.3 hours; SUBQ: 1.5 hours; Intranasal: ~15 minutes (range: ~10 minutes to 3 hours).
Excretion: Urine (<5% as unchanged nalmefene); feces (17%).
Altered kidney function: Plasma clearance was decreased by 27% and 25% in patients with end-stage renal disease (ESRD) during interdialysis and intradialysis, respectively. Elimination half-life was increased to 26.1 ± 9.9 hours in patients with ESRD.
Hepatic function: Plasma clearance was decreased by 28.3% and elimination half-life was increased to ~12 hours in patients with liver disease.
Older adult: Age-related decreases in central volume of distribution may result in increased initial nalmefene concentrations.
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