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Nalmefene (Systemic)


VA CLASSIFICATION
Primary: AD800

Commonly used brand name(s): Revex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Opioid (narcotic) antagonist{01}{02}{03}{04}{05}{06}{07}{08}{09}{18}

Indications

Accepted

Opioid (narcotic) overdose (treatment)—Nalmefene is indicated in the management of known or suspected opioid overdose {01} {03}.

Opioid depression, postoperative (treatment)—Nalmefene is indicated for the complete or partial reversal of the effects induced by natural or synthetic opioids, including respiratory depression {01} {04} {05} {06} {07} {08} {09}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    375.9{01}

Mechanism of action/Effect:

Nalmefene antagonizes the effects of opioids by competing for the opioid receptors in the central nervous system (CNS) {14}. This results in reversal of the effects of the opioid, including reversal of respiratory depression, sedation, and hypotension {01} {02} {03} {04} {05} {06} {07} {08} {09}. Reversal of the analgesic effects of opioids may also occur {01} {05} {07}. Reversal of buprenorphine-induced respiratory depression may be incomplete because buprenorphine has high affinity for opioid receptors, and is displaced from these receptors slowly {01}.


Other actions/effects:

Nalmefene can precipitate withdrawal in patients who are physically dependent on opioid drugs {01}.

Absorption:

Variable in rate, but complete {01}.

Distribution:

At steady state, the volume of distribution is 8.6 L per kg of body weight (L/kg) {01}. Nalmefene is distributed centrally {01}.

Protein binding:

Moderate (45%) {01}.

Biotransformation:

Hepatic, primarily by glucuronide conjugation, but also by dealkylation {01} {14}.

Half-life:


Distribution:

41 (range, 7 to 75) minutes {01} {03}.



Elimination:

10.8 (range, 5.6 to 16) hours {01}.


Onset of action:

Intramuscular and subcutaneous—5 to 15 minutes {01}.

Intravenous—2 to 5 minutes {01}.

Time to peak concentration:

Intramuscular—2.3 hours {01}.

Subcutaneous—1.5 hours {01}.

Note: A secondary plasma peak may occur hours after intravenous injection with nalmefene {15} {17}, perhaps due to enterohepatic recycling {15} {17}.


Time to peak effect:

Dose- and route-dependent {01}.

Duration of action:

Dose- and route-dependent {01} {05} {07} {15} {16} {18}. The duration of action of nalmefene is longer than that of most opioid analgesics and anesthetics {01} {05} {07} {08}. However, partially reversing doses of nalmefene (1 mcg per kg of body weight) have a duration of only 30 to 60 minutes, the time required for nalmefene to redistribute {01} {15}. Fully reversing doses (1 mg per 70 kg of body weight) have a duration of action of many hours {01} {06} {07} {08}. The intramuscular and subcutaneous routes of administration provide an extended duration of action as compared to intravenous administration {01}.

Elimination:
    Renal elimination of unchanged drug (5% to 8%), renal elimination of metabolites (60% to 65%), and fecal elimination (17%) {01}{15}{21}{22}.


In dialysis—
        Removed by dialysis; plasma clearance is reduced 25% during dialysis as compared to clearance in patients with normal renal function {01}.



Precautions to Consider

Carcinogenicity/Tumorigenicity

Studies have not been done to determine the carcinogenic and tumorigenic potential of nalmefene {01}.

Mutagenicity

No mutagenic or clastogenic effect was observed in the Ames test, the mouse micronucleus test, or in the mouse lymphoma assay. Weak clastogenic activity was observed in the human lymphocyte metaphase assay in the absence of exogenous metabolic activation {01}.

Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies in humans have not been done {01}.

In a study in rats, ingestion of 1200 mg per square meter of body surface per day (mg/m²/day) did not affect fertility {01}. Rabbits given up to 2400 mg/m²/day orally or 96 mg/m²/day intravenously did not show impaired fertility {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

No adverse effects were seen in the fetuses of rats and rabbits in studies in which nalmefene was administered orally or intravenously in doses up to 114 times the human dose {01}.

FDA Pregnancy Category B {01}.

Breast-feeding

It is not known if nalmefene is distributed into breast milk {01}. Problems in humans have not been documented {01}.

Nalmefene and its metabolites were distributed into the milk of lactating rats. The concentration of nalmefene in rat milk was about three times the concentration in the plasma 1 hour after a bolus injection, and about one-half the concentration in the plasma 24 hours after the injection {01}.

Pediatrics

No information is available on the relationship of age to the effects of nalmefene in pediatric patients {01}. Safety and efficacy have not been established {01}.


Geriatrics


In a premarketing study comparing the pharmacokinetics of nalmefene in geriatric patients and younger adult patients, no differences were observed in half-life, plasma clearance, or steady-state volume of distribution {01}. However, initial nalmefene serum concentrations were increased in geriatric patients as compared with younger adult patients {01}. Dosing adjustments for age are not recommended in geriatric patients {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Opioid agonist analgesics, including alfentanil, fentanyl, and sufentanil    (nalmefene reverses the analgesic and side effects of opioid agonist analgesics and may precipitate withdrawal symptoms in physically dependent patients being treated for opioid dependence with methadone {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Aspartate aminotransferase (AST [SGOT])    (increases in serum values have been reported {01})


Creatine kinase (CK)    (serum values may be transiently increased; the increases in CK may be related to surgery and not to the administration of nalmefene {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to nalmefene, history of{01}
Risk-benefit should be considered when the following medical problems exist
Cardiac disease    (cardiovascular instability, hypotension, hypertension, pulmonary edema, ventricular fibrillation, and ventricular tachycardia have been reported rarely in connection with opioid reversal in both emergency and postoperative settings, perhaps as a result of abrupt reversal of opioid effects {01})


Opioid dependence or addiction, current    (nalmefene may precipitate withdrawal {01})


Renal function impairment    (dizziness and hypertension may occur following rapid administration of nalmefene in patients with renal function impairment; slow administration of nalmefene is recommended {01})

    (duration of action of nalmefene may be prolonged {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Patient alertness    (although nalmefene has a longer duration of action than other opioid antagonists, resedation is possible, especially when nalmefene is used to reverse the effects of long-acting opioid agonists such as methadone or levomethadyl {01})


» Vital signs    (monitoring of blood pressure, heart rate, and respiratory rate is recommended; patients treated with nalmefene should be monitored until there is no reasonable risk of recurrent respiratory depression; the length of this period of observation depends on the duration of action of the opioid administered {01})




Side/Adverse Effects

Note: Nalmefene caused no serious adverse effects when administered in large intravenous doses to healthy volunteers who had not received an opioid agonist. Many of the side/adverse effects (e.g., agitation, hypertension, nausea, postoperative pain, tachycardia, vomiting) may be caused by the abrupt reversal of the effects of the opioid {01}.
Withdrawal symptoms may be precipitated in patients without previous opioid dependence or addiction when nalmefene is used following surgery for which high doses of opioids were administered {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypertension{01}
    
tachycardia{01} (fast heartbeat)

Incidence less frequent
    
Fever{01}
    
hypotension{01}
    
vasodilatation{01}

Incidence rare
    
Agitation{01}{02}
    
arrhythmia{01} (irregular heartbeat)
    
bradycardia{01} (slow heartbeat)
    
confusion{01}
    
hallucinations{12} (seeing, hearing, or feeling things that are not there)
    
myoclonus{01} (rhythmic movement of muscles)
    
pharyngitis{01} (sore throat)
    
pruritus{01} (itching)
    
urinary retention{01} (difficult urination)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dizziness{01}{08}{11}{15}
    
nausea{01}{03}{08}{11}
    
pain, postoperative{01}
    
vomiting{01}{03}{08}

Incidence less frequent
    
Chills{01}
    
headache{01}





Overdose
Healthy volunteers injected with 24 mg of nalmefene did not experience overdose effects {01} {15}. Treatment of patients dependent on opioids with nalmefene can cause adverse effects, but the adverse effects are caused by reversal of opioid effects {01}. This is most likely to occur if fully blocking doses are administered {01}. Treatment of withdrawal reactions should be symptomatic and supportive {01}. Use of opioids to overcome full blockade is not recommended because this has resulted in adverse respiratory and cardiovascular effects {01}.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).


General Dosing Information
Treatment with nalmefene for ventilatory failure should not precede usual emergency measures such as securing a patent airway, administering oxygen, assisting ventilation, and establishing circulatory access {01}.

Nalmefene is available in two concentrations, in ampuls with color-coded labels: the 100-mcg-per-mL (mcg/mL) concentration has a blue label, and the 1-mg-per-mL (mg/mL) concentration has a green label {01}. The 100-mcg/mL concentration is suitable for routine postoperative use, and the 1-mg/mL concentration is suitable for the management of overdose {01}.

Lack of clinical response in sedation and/or respiratory depression after administration of nalmefene in sufficient dosage usually indicates that the conditions are not caused by an opioid {01} {03}. It is recommended that nalmefene be administered to reverse sedation and hypoventilation only when it is likely that opioid administration is responsible {01}. However, in preclinical animal testing, nalmefene did not completely reverse the analgesic effects of buprenorphine, even when very high doses of nalmefene were administered {01}. Nalmefene may not be effective in reversing buprenorphine-induced sedation and respiratory depression {01}.

Nalmefene may cause withdrawal symptoms in patients tolerant to or dependent on opioids {01}. If nalmefene is used when there is concern about opioid dependency, a test dose of 0.1 mg per 70 kg of body weight should be administered {01}. If there is no evidence of withdrawal after 2 minutes, the full dose may be administered {01}. Following each injection of nalmefene, patients should be observed closely for withdrawal symptoms {01}. Subsequent doses should be administered after 2 to 5 minutes to allow the full effect of each incremental dose to be reached {01}.

When nalmefene is used to reverse the effects of opioid agonists used as anesthesia adjuncts, the dosage of nalmefene must be carefully titrated in order to achieve the desired effect without interfering with control of postoperative pain or causing other adverse effects {01}.

The duration of action of nalmefene exceeds the duration of action of most opioids. However, if recurrence of sedation and/or respiratory depression occurs, nalmefene should be administered and titrated to clinical effect {01}.

The long duration of action of nalmefene could cause patients to be without opiate analgesia for an extended period of time if fully reversing doses of nalmefene are administered after surgical procedures {01} {05} {07} {15} {16} {18}. Additionally, patients may experience increased sensitivity to pain after receiving nalmefene, possibly due to blocking of endogenous neuropeptides {04} {06}.

In premarketing clinical trials, intravenous nalmefene was effective in reversing respiratory depression in patients given intrathecal morphine {01} {19}. Administration of nalmefene at the recommended doses did not prevent analgesia with subsequently administered opioids {01} {19}.


Parenteral Dosage Forms

Note: The dosing and strengths of the dosage form available are expressed in terms of nalmefene base (not the hydrochloride salt) {01}.


NALMEFENE HYDROCHLORIDE INJECTION

Usual adult dose
Management of opioid overdose
Intravenous, 0.5 mg (base) per 70 kg of body weight initially {01}. If needed, a second dose of 1 mg per 70 kg of body weight can be administered two to five minutes later. {01} Nalmefene may be administered by intramuscular or subcutaneous injection if intravenous access is lost or cannot be obtained {01}. Intramuscular or subcutaneous injections should be effective within five to fifteen minutes {01}.

Reversal of postoperative opioid depression
Intravenous, 0.25 mcg (base) per kg of body weight at two- to five-minute intervals, stopping when the desired degree of reversal is achieved {01}.


Note: Nalmefene should be carefully titrated. The recommended doses of nalmefene balance the need for rapid onset of action and reasonable duration of action against achieving a controlled reversal {01}. Using higher doses or shorter intervals between incremental doses increases the likelihood of reversing analgesia and causing the patient to experience symptoms related to acute withdrawal, such as nausea, vomiting, increased blood pressure, and agitation {01}. Once adequate reversal has been established, additional administration is not recommended {01}.
For patients with increased risk of cardiovascular complications, it is recommended that the dose of nalmefene be diluted in an equal amount of normal saline or sterile water, and administered in increments of 0.1 mcg per kg of body weight {01}.


Usual adult prescribing limits
Management of opioid overdose
1.5 mg per 70 kg of body weight {01}.

Reversal of postoperative opioid depression
1 mcg per kg of body weight {01}.


Usual pediatric dose
Safety and efficacy have not been established {01}.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


100 mcg (base) per mL (Rx) [Revex{01}]


1 mg (base) per mL (Rx) [Revex{01}]

Canada—


100 mcg (base) per mL (Rx) [Revex{20}]


1 mg (base) per mL (Rx) [Revex{20}]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF) {01}.



Revised: 09/20/1999



References
  1. Product Information: REVEX ®, nalmefene hydrochloride injection. Ohmeda Pharmaceutical Products, Liberty Corner, NJ, USA, 1995.
  1. Fudula P, Heishman S, Henningfield J, et al. Human pharmacology and abuse potential of nalmefene. Clin Pharmacol Ther 1991; 49: 300-6.
  1. Kaplan J, Marx J. Effectiveness and safety of intravenous nalmefene for emergency department patients with suspected narcotic overdose: a pilot study. Ann Emerg Med 1993; 22: 187-90.
  1. Konieczko K, Jones J, Barrowcliffe M, et al. Antagonism of morphine-induced respiratory depression with nalmefene. Br J Anaesth 1988; 61: 318-23.
  1. Gal T, DiFazio C, Dixon R. Prolonged blockade of opioid effect with oral nalmefene. Clin Pharmacol Ther 1986; 40: 537-42.
  1. Moore L, Bikhazi G, Tuttle R, et al. Antagonism of fentanyl-induced respiratory depression with nalmefene. Methods Find Exp Clin Pharmacol 1990; 12: 29-35.
  1. Gal T, DiFazio C. Prolonged antagonism of opioid action with intravenous nalmefene in man. Anesthesiology 1986; 64: 175-80.
  1. Barsan W, Seger D, Danzl D, et al. Duration of antagonistic effects of nalmefene and naloxone in opiate-induced sedation for emergency department procedures. Am J Emerg Med 1989; 7: 155-61.
  1. Mikati H, Bikhazi G, Foldes F. Antagonism of the respiratory depressant effect of fentanyl by nalmefene. Anesth Analg 1989; 68: S195.
  1. Hold.
  1. Mason B, Rivto E, Morgan R, et al. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994; 18: 1162-7.
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  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995. p. 474.
  1. Landymore K, Giles A, Wilkinson M, et al. Ex vivo determination of opiate antagonist binding at mu-opioid ([³H]-Dago) receptors in hypothalamic micropunches from maturing female rats: comparison between SDZ 210-096 and nalmefene. Neuropeptides 1992; 21: 175-82.
  1. Dixon R, Howes J, Gentile J, et al. Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986; 39: 49-53.
  1. Levison B, Reynolds R, Kisicki J, et al. The pharmacokinetics of nalmefene, an opioid antagonist [abstract]. Anesthesiology 1990; 73(3A): A356.
  1. Chou J, Albeck H, Kreek M. Determination of nalmefene in plasma by high performance liquid chromatography with electrochemical detection and its application in pharmacokinetic studies. J Chromatogr 1993; 613: 359-64.
  1. Glass P, Jhaveri R, Smith L, et al. Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg 1994; 78: 536-41.
  1. Lowdon JD, Yeung L, Isaacson I, et al. Nalmefene for reversal of respiratory depression secondary to intrathecal morphine [abstract]. Anesthesiology 1990; 73(3A): A385.
  1. Revex package insert (Ohmeda—Canada), Rev 10/96, Rec 2/97.
  1. Dixon R, Gentile J, Hsu H-B et al: Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist. J Clin Pharmcol 1987; 27: 233–239.
  1. Frye RF, Matzke GR, Jallad JA et al: The effect of age on the pharmacokinetics of the opioid antagonist nalmefene. Br J Clin Pharmacol 1996; 42: 301–306.

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